Vegfr3 inhibitors

ABSTRACT

This invention relates to compounds of the formula (I). The invention also relates to processes for the preparation of the compound of the formula (I), pharmaceutical agents or compositions containing the compound or a method of using the compound for the treatment of proliferative diseases, such as cancer as well as the treatment of diseases ameliorated by the control and/or inhibition of lymphanglogenesis.

This invention relates to 2,4,5-substituted pyrimidines that inhibitvascular endothelial growth factor receptor 3 (VEGFR3), also known asFms related tyrosine kinase 4 (FLT4), processes for their preparation orpharmaceutical agents or compositions containing such compounds. Thisinvention also relates to a method of using such compounds for thetreatment of proliferative diseases, such as cancer, as well as thetreatment of diseases ameliorated by the control and/or inhibition oflymphangiogenesis.

BACKGROUND

Cancer remains a major cause of death in the 21st century. Consequently,considerable drug research and development effort is currently placed onthe discovery of therapeutics that may provide life extending orcurative options to cancer sufferers.

While there are many different varieties of cancer, each exhibiting adifferent array of genetic and growth properties, a common denominatoramong many solid cancer types is the ability to metastasize. Until theoccurrence of metastasis, tumors are confined to one area of the bodyand may be controlled through surgical intervention and/or radiotherapy.However, metastasis causes cancer cells to spread to disparate parts ofthe body and while surgical intervention may remove the primary tumorlesion, removal of all metastatic lesions is very difficult to manage.

Tumor metastasis is a multistage process, involving the breakdown ofextracellular matrix, invasion of local tissue parenchyma, intravasationinto regional blood vessels and lymphatics, survival in the circulationand finally extravasation, survival and growth in secondary tissue sites(Front. Biosci. (Elite Ed). 2012; 4: 1888-1897).

Metastasis may occur through blood vessels or lymphatic vessels.Lymphatic vessels differ from blood vessels in several ways. Largecollecting lymphatic vessels contain vascular smooth muscle cells intheir wall, as well as valves, which prevent the backflow of lymph.However, lymphatic capillaries, unlike typical blood capillaries, lackpericytes and continuous basal lamina and contain largeinter-endothelial valve-like openings (J. Theor. Med. 2003; 5: 59-66).Due to their greater permeability, lymphatic capillaries are moreeffective than blood capillaries in allowing tumor cells to pass.Experimental evidence demonstrates that lymphangiogenesis (the formationof new lymphatic vessels) within a growing tumor lesion promotesmetastasis through lymphatic vessels. The control of lymphangiogenesispresents an attractive therapeutic strategy for preventing lymph nodemetastasis (J. Clin. One. 2007; 25: 4298-4307).

The lymphatic system is comprised of capillaries and larger collectingvessels continuously lined by endothelial cells which returnextravasated fluid and macromolecules from the interstitial space backto the blood circulation. Metastasis to regional lymph nodes vialymphatic vessels is a tumor progression process that is common to manycancer types. The extent of lymph node involvement is a majordeterminant for the staging of many types of cancer and is an importantprognostic factor that is used as the basis for surgical and radiationtreatment intervention of the affected lymph nodes.

Molecular signalling through binding of the growth factors VEGFC orVEGFD to their membrane receptor VEGFR3 has been shown to play a centralrole in the process of lymphangiogenesis (Brit. J. Cancer 2006; 94:1355-1360). Stimulation of the VEGFR3 receptor occurs through thephosphorylation of its intracellular region and triggers a downstreamsignalling cascade that drives lymphatic endothelial cell proliferation,migration and differentiation leading to formation of lymphatic vessels(Exp. Cell Res. 2006; 312: 575-583). Increased expression of VEGFC orVEGFD has been shown to promote tumor associated lymphangiogenesisenabling lymphatic-mediated metastasis to regional lymph nodes. Theseobservations have been reported for several different tumor types,including colorectal (Oncol. Rep. 2009; 22: 1093-1100) lung (Ann. Oncol.2010; 21: 223-231), gastric (Surgery 2009; 146: 896-905), kidney (Oncol.Rep. 2008; 20: 721-725) prostate (Clin. Cancer Res. 2004; 10: 5137-5144)and ovarian (Cancer 2004; 101: 1364-1374). Blockade of VEGFC,VEGFD/VEGFR3 mediated signalling has been shown to inhibitlymphangiogenesis and suppress lymph node metastasis in several tumorexperimental models in rodents (Ann. N.Y. Acad. Sci. 2008; 113: 225-234;Int. J. Cancer 2009; 125: 2747-2756). VEGFR3 is a transmembrane tyrosinekinase receptor that is broadly expressed in endothelial cells duringembryogenesis (Biochem. J. 2011; 437: 169-183). In the latter stages ofdevelopment VEGFR3 expression becomes restricted to developing lymphaticvessels. In adults, VEGFR3 expression is primarily restricted tolymphatic endothelium and a subset of CD34+ hematopoietic cells. Inaddition, fenestrated capillaries and veins in certain endocrine organs,as well as monocytes, macrophages and some dendritic cells (DCs),continue to express VEGFR3 in adults. Disruption of the VEGFR3 gene inmouse embryos results in the failure of vascular network formation anddeath after embryonic day 9.5 (Biochem. J. 2011; 437: 169-183). Thisobservation demonstrates that VEGFR3 plays an essential role in thedevelopment of embryonic vasculature. In cancer, VEGFR3 is overexpressedin lymphatic sinuses in metastatic lymph nodes and in lymphangiomas.Furthermore, in many instances cancer cells themselves express VEGFR3.VEGFR3 expressing cancer cells have been shown to be dependent onVEGFR3/VEGFC signalling for their proliferation (Eur. J. Canc. 2011; 47:2353-2363).

Based on the foregoing, it is apparent that inhibition of VEGFR3signalling has strong potential as therapeutic strategy for mammaliansubjects that have been diagnosed with a disease characterised byproliferation of endothelial cells that express this receptor. In thecase of cancer, targeting VEGFR3 is likely to result in therapeuticbenefit through suppression of lymphatic metastasis and suppression ofgrowth in cancer cells that express VEGFR3.

Interestingly, and perhaps importantly from the view point of targetselection within the VEGFR3 axis, in mice in which both the VEGFC andthe VEGFD genes have been homozygously deleted, the blood vasculaturedevelops normally, unlike the embryonic cardiovascular phenotype ofVEGFR3 homozygous knockout mice: i.e. deletion of these two ligands isnot the same as deletion of the receptor (Mol. Cell. Biol. 2008; 28:4843-4850). These data raise the possibility that another ligand forVEGFR3 exists or that VEGFR3 may be able to act by an as-yet-unknownmanner independent of its ligands VEGFC and VEGFD. The foregoing suggestthat targeting VEGFR3 is more advantageous to blocking VEGFC/D-VEGFR3signalling compared to targeting either VEGFC or VEGFD alone.

Whilst there are a number of studies reported involving tyrosine kinaseinhibitors with various levels of VEGFR3 activity and selectivity (Nat.Rev. Drug Discov. 2006; 5: 835-844; Mol. Cancer. Ther. 2007; 6:2012-2021; Cancer Res. 2009; 69: 8009-8016; Mol. Cancer. Ther. 2012; 11:1637-1649) these studies have some limitations, resulting in part atleast from inhibition at other tyrosine kinases.

Nonetheless, collectively these studies strengthen the conclusion thatinhibition of VEGFR3 suppresses or reduces lymphangiogenesis and/orlymphogenic metastasis.

Accordingly, compounds that selectively inhibit VEGFR3 would be usefulfor the treatment of proliferative diseases, such as cancer.

As described above, VEGFR3 plays an important role in the control oflymphangiogenesis. Accordingly, inhibitors of VEGFR3 may have utility inthe treatment of diseases other than cancer where control/inhibition oflymphangiogenesis has a therapeutic benefit. The lymphatic system playsa major role in chronic inflammatory diseases and in transplantrejection. Inhibition of lymphangiogenesis through suppression of VEGFR3function may provide a viable therapeutic strategy in these conditions.

For example, preclinical studies have demonstrated that the expressionof VEGFR3 in the cornea and ocular surface is modified during cornealneovascularisation and that VEGFR3 mediates corneal dendritic cellmigration to lymph nodes and induction of immunity to cornealtransplant. High-risk corneal transplantation, where grafting isperformed on inflamed and highly vascularized host beds, has a very poorsuccess rate, with rejection rates as high as 90% (J. Leukoc Biol. 2003;74: 172-178). In preclinical models, treatment with a VEGFR3 antibodyleads to significant suppression of corneal graft rejection (Nat. Med.2004; 10: 813-815).

Choroidal neovascularization (CNV), the creation of new blood vessels inthe choroid layer of the eye, leads to chronic inflammation which isimplicated in the pathogenesis of age related macular degeneration (AMD)and is driven by factors which include uncontrolled expression of thevascular endothelial growth factor (VEGF) family members VEGFA and VEGFC(J. Cell. Physiol. 2012; 227(1): 116-26). Treatments for AMD have beendeveloped that target VEGFA, for example the anti-VEGFA antibodiesranibizumab and bevacizumab and the anti-VEGF aptamer pegaptanib, but todate no treatments have been clinically evaluated that mediate effectsthrough modulation of VEGFC and its cognate receptor VEGFR3.

Accordingly, compounds that inhibit VEGFR3 may be useful for theprevention and/or treatment of eye diseases, for example corneal graftrejection and age related macular degeneration.

Furthermore, there is increasing evidence that lymphatic vessels have anactive role in chronic inflammation of the skin. Lymphatic endothelialcell proliferation and lymphatic hyperplasia have been described inchronic skin inflammation in mice and have been reported for skinlesions in psoriasis patients (Blood 2004; 104: 1048-1057). Accordingly,compounds that inhibit VEGFR3 may be useful for the prevention and/ortreatment of skin inflammations, such as skin lesions in patients withpsoriasis. Lymphangiogenesis has also been found to be associated withkidney transplant rejection. VEGFC producing macrophages induceformation of new lymphatics which induce and support the maintenance ofan alloreactive immune response in renal transplants (Nat. Med. 2006;12: 230-234).

Accordingly, compounds that inhibit VEGFR3 may be useful for theprevention and/or treatment of rejection in renal transplantation.

Co-pending application PCT/GB2012/000175 discloses compounds whichinhibit FAK and VEGFR3.

SUMMARY

The present inventors have discovered a particular class of compoundswhich are effective as VEGFR3 inhibitors. These compounds may exhibitselectivity for VEGFR3 over kinases such as FAK and/or VEGFR2.

In a first aspect, the present invention provides compounds of thefollowing formula (I) or isomers, salts, solvates or prodrugs thereof:

wherein:

A is an optionally substituted 5-10 membered heteroaryl group linked tothe NH group through an aromatic ring carbon atom, in which theheteroaryl ring system contains 1 to 4 heteroatoms selected from N, Oand S; and

A may bear a single substituent R^(1A) which is not alpha to the NHgroup, and may optionally further bear one, two or three substituentsR^(1C), where R^(1A) is selected from:

-   -   (i) CH(R^(C1))NHZ¹, where R^(C1) is selected from H, C₁₋₂ alkyl        and Z¹ is selected from H, C₁₋₃ alkyl optionally substituted by        OH, C(═O)OC₁₋₃ alkyl and C(═O)Me;    -   (ii) XNHZ², where X is selected from CMe₂, cyclopropylidene,        cyclobutylidene, cyclopentylidene and oxetanylidine and Z² is        selected from H, C₁₋₃ alkyl optionally substituted by OH,        C(═O)OC₁₋₃ alkyl and C(═O)Me;    -   (iii) a group selected from R^(1A1) to R^(1A11);

-   -   wherein:        -   R^(N1) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N2) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N3) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N4) is selected from H and CH₃;        -   R^(N5) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N6) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N7) and R^(N8) are independently selected from H and CH₃;        -   R^(N9) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N10) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N11) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me; and        -   R^(N12) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;    -   and where each R^(1C) is independently selected from:    -   (i) C₁₋₃ alkyl;    -   (ii) CF₃;    -   (iii) F;    -   (iv) Cl;    -   (v) O—(C₁₋₃ alkyl);    -   (vi) CN; and    -   (vii)═O;    -   R² is selected from H, halo, C₁₋₄ alkyl, CF₃, CF₂H, CN and        methoxy;    -   R³ is selected from substituted phenyl and a substituted 6        membered heteroaryl group, where the heteroaryl ring system        contains 1 or 2 N heteroatoms, where    -   R³ bears a substituent R⁴ either alpha or beta to the —C₂H₄—        group, and may additionally bear further substituents selected        from F, methyl and CF₃; and    -   R⁴ is —CH₂—C(O)N(R^(N13))Z³, where R^(N13) is selected from H        and CH₃; and Z³ is selected from H, CH₃ and OCH₃.

In some embodiments, the compounds of the first aspect of the presentinvention are of formula (I) as defined above with the proviso that thecompound is not:

In a second aspect, the present invention provides compounds of thefollowing formula (II) or isomers, salts, solvates or prodrugs thereof:

wherein:

A is optionally substituted phenyl;

when A is optionally substituted phenyl, A may bear a substituent R^(1A)which is not alpha to the NH group and may optionally further bear oneor two substituents R^(1B) which are not alpha to the NH group, whereR^(1A) is selected from:

-   -   (i) CH(R^(C1))NHZ¹, where R^(C1) is selected from H, C₁₋₂ alkyl        and Z¹ is selected from H, C₁₋₃ alkyl optionally substituted by        OH, C(═O)OC₁₋₃ alkyl and C(═O)Me;    -   (ii) XNHZ², where X is selected from CMe₂, cyclopropylidene,        cyclobutylidene, cyclopentylidene and oxetanylidine and Z² is        selected from H, C₁₋₃ alkyl optionally substituted by OH,        C(═O)OC₁₋₃ alkyl and C(═O)Me;    -   (iii) a group selected from R^(1A1) to R^(1A11):

-   -   wherein:        -   R^(N1) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N2) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N3) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N4) is selected from H and CH₃;        -   R^(N5) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N6) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N7) and R^(N8) are independently selected from H and CH₃;        -   R^(N9) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N10) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N11) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me; and        -   R^(N12) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;    -   and where each R_(1B) is independently selected from:    -   (i) C₁₋₃ alkyl;    -   (ii) CF₃;    -   (iii) F;    -   (iv) Cl;    -   (v) O—(C₁₋₃ alkyl); and    -   (vi) CN;    -   R² is selected from H, halo, C₁₋₄ alkyl, CF₃, CF₂H, CN and        methoxy;    -   R³ is selected from substituted phenyl and a substituted 6        membered heteroaryl group, where the heteroaryl ring system        contains 1 or 2 N heteroatoms, where    -   R³ bears a substituent R⁴ either alpha or beta to the —C₂H₄—        group, and may additionally bear further substituents selected        from F, methyl and CF₃; and    -   R⁴ is —CH₂—C(O)N(R^(N13))Z³, where R^(N13) is selected from H        and CH₃; and Z³ is selected from H, CH₃ and OCH₃.

In some embodiments, the compounds of the second aspect of the presentinvention are of formula (II) or isomers, salts, solvates or prodrugsthereof as defined above with the proviso that the compound is not anyof the following compounds:

In some embodiments, the compounds of the second aspect are of formula(II) as defined above with the proviso that:

when R³ is selected from:

A is either:

where R^(1A) is selected from

and

-   -   R^(N1) is selected from H, C₁₋₃ alkyl, and C(═O)Me;    -   R^(N2) is selected from H, C₁₋₃ alkyl, and C(═O)Me;    -   R^(N3) is selected from H, C₁₋₃ alkyl, and C(═O)Me;    -   R^(N4) is selected from H and CH₃;    -   R^(N5) is selected from H, C₁₋₃ alkyl, and C(═O)Me;    -   R^(N7) and R^(N8) are independently selected from H and CH₃;    -   R^(N9) is selected from H, C₁₋₃ alkyl, and C(═O)Me;    -   R^(N10) is selected from H, C₁₋₃ alkyl, and C(═O)Me; or

-   -   where R^(1A) is

-   -   and R^(N1) is selected from H, C₁₋₃ alkyl, and C(═O)Me;    -   R^(N2) is selected from H, C₁₋₃ alkyl, and C(═O)Me;    -   then R² is not selected from CF₃, halo, CF₂H and CN.

A third aspect of the invention provides a process for the preparationof a compound of formula (I) or formula (II) or isomers, salts, solvatesor prodrugs thereof of either the first aspect or the second aspect,comprising reacting a compound of formula F1

-   -   with a compound of formula A-NH₂ to displace the group L¹ and        with a compound of formula HC≡R³ to displace the group L²; or    -   with a compound of formula HC≡R³ to displace the group L² and        with a compound of formula A-NH₂ to displace the group L¹,    -   wherein A, R² and R³ are as defined in formula (I) or (II) above        and L¹ and L² are leaving groups.

A fourth aspect of the invention provides a pharmaceutical agentcomprising a compound of the formula (I) or formula (II) or isomers,salts, solvates or prodrugs thereof of either the first aspect or thesecond aspect.

There is also provided use of a compound of formula (I) or formula (II)or isomers, salts, solvates, protected forms or prodrugs thereof ofeither the first aspect or the second aspect as a pharmaceutical agent.

There is further provided a compound of formula (I) or formula (II) orisomers, salts, solvates or prodrugs thereof of either the first aspector the second aspect for use as a pharmaceutical agent.

The pharmaceutical agent may be an anticancer agent, a lyphangiogenesisinhibitor, an antimetatstasis agent or a HVEGFR3 inhibitor.

A fifth aspect of the present invention provides a compositioncomprising a compound of formula (I) or formula (II) or an isomer, salt,solvate or prodrug thereof of either the first aspect or the secondaspect and a pharmaceutically acceptable carrier or diluent.

A sixth aspect of the invention provides a compound of formula (I) orformula (II) or an isomer, salt, solvate or prodrug thereof of eitherthe first aspect or the second aspect, agent of the fourth aspect orcomposition of the fifth aspect for use in a method of therapy.

A seventh aspect of the invention provides for the use of a compound offormula (I) or formula (II) or an isomer, salt, solvate or prodrugthereof, of either the first aspect or the second aspect, agent of thefourth aspect or composition of the fifth aspect in the preparation of amedicament for treating a disease or condition ameliorated by theinhibition of VEGFR3. The seventh aspect of the invention also providesa compound of formula (I) or (II) of either the first aspect or thesecond aspect, agent of the fourth aspect or composition of the fifthaspect for use in the method of treatment of a disease or conditionameliorated by the inhibition of VEGFR3.

An eighth aspect of the invention provides for the use of a compound offormula (I) or formula (II) or an isomer, salt, solvate or prodrugthereof of either the first aspect or the second aspect, agent of thefourth aspect or composition of the fifth aspect in the preparation of amedicament for treating cancer. The eighth aspect of the invention alsoprovides a compound of formula (I) or formula (II) or an isomer, salt,solvate or prodrug thereof of either the first aspect or the secondaspect, agent of the fourth aspect or composition of the fifth aspectfor use in the method of treatment of cancer.

A further aspect of the invention provides a compound of formula (I) orformula (II) or an isomer, salt, solvate or prodrug thereof of eitherthe first aspect or the second aspect, agent of the fourth aspect orcomposition of the fifth aspect for use in a method of treatment of thehuman or animal body, preferably in the form of a pharmaceuticalcomposition.

Another aspect of the invention provides a method of inhibiting VEGFR3in vitro or in vivo, comprising contacting a cell or cell lysates withan effective amount of a compound of formula (I) or formula (II) or anisomer, salt, solvate or prodrug thereof of either the first aspect orthe second aspect, agent of the fourth aspect or composition of thefifth aspect.

A still further aspect of the invention provides an anti-cancertreatment comprising a compound of formula (I) or formula (II) or anisomer, salt, solvate or prodrug thereof of either the first aspect orthe second aspect, agent of the fourth aspect or composition of thefifth aspect and an anti-tumour agent.

Each of the groups A, and R¹ to R⁴ from the first and second aspects ofthe invention will be discussed in more detail below.

A

A is selected from optionally substituted phenyl (in the second aspectof the invention) and an optionally substituted 5-10 membered heteroarylgroup linked to the NH group through an aromatic ring carbon atom (inthe first aspect of the invention), in which the heteroaryl ring systemcontains 1 to 4 heteroatoms selected from N, O and S.

If A is unsubstituted phenyl, it has the structure:

If A is substituted phenyl, the R^(1A) group can either be meta or para,and so A can have the structures:

where the R_(1B) group cannot be alpha to the connection point to therest of the compound (i.e., it cannot be in the asterixed positions).

When A is a 5-10 membered heteroaryl group linked to the NH groupthrough an aromatic ring carbon atom, in which the heteroaryl ringsystem contains 1 to 4 heteroatoms selected from N, O and S, it is amonovalent moiety obtained by removing a hydrogen atom from an aromaticring atom of an heteroaromatic compound (i.e. a compound having at leastone heteroaromatic ring), which moiety has from 5 to 10 ring atoms.Preferably, each ring has from 5 to 7 ring atoms.

Examples of monocyclic heteroaryl groups include, but are not limitedto, those derived from:

-   -   N1: pyrrole (azole) (5-membered), pyridine (azine) (6-membered);    -   O1: furan (oxole) (5-membered);    -   S1: thiophene (thiole) (5-membered);    -   N₁O₁: oxazole (5-membered), isoxazole (5-membered), isoxazine        (6-membered);    -   N₂O₁: oxadiazole (furazan) (5-membered);    -   N₃O₁: oxatriazole (5-membered);    -   N₁S₁: thiazole (5-membered), isothiazole (5-membered);    -   N_(2:) imidazole (1,3-diazole) (5-membered), pyrazole        (1,2-diazole) (5-membered), pyridazine (1,2-diazine)        (6-membered), pyrimidine (1,3-diazine) (6-membered) (e.g.,        cytosine, thymine, uracil), pyrazine (1,4-diazine) (6-membered);    -   N_(3:) triazole (5-membered), triazine (6-membered); and,    -   N_(4:) tetrazole (5-membered).

Examples of heteroaryl groups which comprise fused rings, include, butare not limited to, those derived from:

-   -   9-membered (with 2 fused rings) derived from benzofuran (O₁),        isobenzofuran (O₁), indole (N₁), isoindole (N₁), indolizine        (N₁), indoline (N₁), isoindoline (N₁), purine (N₄) (e.g.,        adenine, guanine), benzimidazole (N₂), indazole (N₂),        benzoxazole (N₁O₁), benzisoxazole (N₁O₁), benzodioxole (O₂),        benzofurazan (N₂O₁), benzotriazole (N₃), benzothiofuran (S₁),        benzothiazole (N₁S₁), benzothiadiazole (N₂S);    -   10-membered (with 2 fused rings) derived from chromene (O₁),        isochromene (O₁), chroman (O₁), isochroman (O₁), benzodioxan        (O₂), quinoline (N₁), isoquinoline (N₁), quinolizine (N₁),        benzoxazine (N₁O₁), benzodiazine (N₂), pyridopyridine (N₂),        quinoxaline (N₂), quinazoline (N₂), cinnoline (N₂), phthalazine        (N₂), naphthyridine (N₂), pteridine (N₄).

Thus, when A is a 5 to 10 membered heteroaryl group, it may be selectedfrom any of the groups listed above.

In some embodiments, A is a 5 or 6 membered heteroaryl group linked tothe NH group through an aromatic ring carbon atom, in which theheteroaryl ring system contains 1 or 2 heteroatoms selected from N, Oand S. Preferably the heteroatoms are N atoms.

If A is 6-membered heteroaryl, the R^(1A) group can either be meta orpara to the NH group. If A is 5-membered heteroaryl or a 7 to 10membered heteroaryl, the R^(1A) group is not alpha to the —NH— group.Thus, when A is 5-membered heteroaryl, the R^(1A) group is beta to the—NH— group

-   -   R^(1A)    -   R^(1A) may have one of the following structures:    -   CH₂NHZ¹;    -   CH(CH₃)NHZ¹;    -   CH(C₂H₅)NHZ¹;

-   -   wherein:        -   R^(N1) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N2) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N3) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N4) is selected from H and CH₃;        -   R^(N5) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N6) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N7) and R^(N8) are independently selected from H and CH₃;        -   R^(N9) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N10) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me;        -   R^(N11) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me; and        -   R^(N12) is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and            C(═O)Me.

Each of R^(N1), R^(N2), R^(N3), R^(N5), R^(N6), R^(N9), R^(N10), R^(N11)and R^(N12) is independently selected from H, C₁₋₄ alkyl (i.e. methyl,ethyl, prop-1-yl, prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl),C₃₋₄ cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) andC(═O)Me. Each of R^(N4), R^(N7) and R^(N8) is independently selectedfrom either H or methyl.

Each of Z¹ and Z² is independently selected from H, C₁₋₃ alkyl (i.e.methyl, ethyl, prop-1-yl and prop-2-yl), optionally substituted by OH,C(═O)OC₁₋₃ alkyl (i.e. C(═O)O-methyl, C(═O)O-ethyl, C(═O)O-prop-1-yl andC(═O)O-prop-2-yl) and C(═O)Me.

R_(1B)

Each R_(1B) group may be C₁₋₃ alkyl (i.e. methyl, ethyl, prop-1-yl andprop-2-yl), CF₃, F, Cl, O—C₁₋₃ alkyl (i.e. methoxy, ethoxy, prop-1-oxyand prop-2-oxy) or CN. These groups may be any available ring positionon A, except that which is alpha to the NH group. There may be up to 2R_(1B) groups (i.e. 1 or 2).

R^(1C)

Each R^(1C) group may be C₁₋₃ alkyl (i.e. methyl, ethyl, prop-1-yl andprop-2-yl), CF₃, F, Cl, O—C₁₋₃ alkyl (i.e. methoxy, ethoxy, prop-1-oxyand prop-2-oxy), CN or ═O. These groups may be substituted at anyavailable ring position on A. There may be up to 3 R^(1C) groups (i.e.1, 2 or 3) depending on the nature of A, and in particular on the numberof ring atoms and ring heteroaroms, as well as whether R^(1A) ispresent.

R²

R² is selected from H, halo (i.e. F, Cl, Br, I), C₁₋₄ alkyl (i.e.methyl, ethyl, prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl,tert-butyl), CF₃, CF₂H, CN and methoxy. In some embodiments, the halogroup is either F or Cl.

R³

R³ is selected from substituted phenyl and a substituted 6 memberedheteroaryl group, where the heteroaryl ring system contains 1 or 2 Nheteroatoms.

When R³ is substituted phenyl, it has the structure:

where R⁶, R⁷ and R⁸ are independently selected from H, F, methyl andCF₃. One of R^(4A) and R^(4B) is R⁴, and the other is selected from H,F, methyl and CF₃.

When R³ is a substituted 6 membered heteroaryl group, where theheteroaryl ring system contains 1 or 2 N heteroatoms, it may be selectedfrom the any of the groups: pyridyl; pyridazinyl (1,2-diazinyl);pyrimidinyl (1,3-diazinyl); and pyrazinyl (1,4-diazinyl).

When R³ is a substituted 6 membered heteroaryl group, it may have one ofthe following structures:

where R⁶, R⁷ and R⁸ (if present) are independently selected from H, F,methyl and CF₃. One of R^(4A) and R^(4B) (if present) is R⁴, and theother is selected from H, F, methyl and CF₃.

When R⁴ is alpha to the —C₂H₄-group, it may also be described as beingortho. When R⁴ is beta to the —C₂H₄-group, it may also be described asbeing meta.

The further optional substituents on R³ are independently selected fromF, methyl and CF₃. These further groups may be at any available ringposition on R³, except that occupied by R⁴. There may be upto 4 furtheroptional substituents groups (i.e. 1, 2, 3 or 4) depending on the natureof R³, and in particular on the number of ring heteroaroms.

R⁴

R⁴ is —CH₂—C(O)N(R^(N13))Z³.

R^(N13) is selected from H and CH₃, and Z³ is selected from H, CH₃ orOCH₃. Thus, R⁴ is selected from:

-   -   (i) —CH₂—C(O)NH₂;    -   (ii) —CH₂—C(O)NHMe;    -   (iii) —CH₂—C(O)NMe₂;    -   (iv) —CH₂—C(O)N(OMe)H;    -   (v) —CH₂—C(O)N(OMe)Me.

Proviso

In some embodiments of the second aspect, compounds of WO2012/110773 aredisclaimed from the present application (C1-C32 below):

In other embodiments of the second aspect, the compounds of the presentinvention do not include those disclosed in WO2012/110773, which isincorporated herein by reference. In particular, when R³ is selectedfrom:

A is either:

where R^(1A) is selected from

-   -   and R^(N1) is selected from H, C₁₋₃ alkyl, and C(═O)Me;    -   R^(N2) is selected from H, C₁₋₃ alkyl, and C(═O)Me;    -   R^(N3) is selected from H, C₁₋₃ alkyl, and C(═O)Me;    -   R^(N4) is selected from H and CH₃;    -   R^(N5) is selected from H, C₁₋₃ alkyl, and C(═O)Me;    -   R^(N7) and R^(N8) are independently selected from H and CH₃;    -   R^(N9) is selected from H, C₁₋₃ alkyl, and C(═O)Me;    -   R^(N10) is selected from H, C₁₋₃ alkyl, and C(═O)Me; or

where R^(1A) is

-   -   and R^(N1) is selected from H, C₁₋₃ alkyl, and C(═O)Me;    -   R^(N2) is selected from H, C₁₋₃ alkyl, and C(═O)Me;    -   then R² is not selected from CF₃, halo, CF₂H and CN.

Includes Other Forms

Included in the above are the well known ionic, salt, solvate, andprotected forms of these substituents. For example, a reference tocarboxylic acid (—COOH) also includes the anionic (carboxylate) form(—COO⁻), a salt or solvate thereof, as well as conventional protectedforms. Similarly, a reference to an amino group includes the protonatedform (—N⁺HR¹R²), a salt or solvate of the amino group, for example, ahydrochloride salt, as well as conventional protected forms of an aminogroup. Similarly, a reference to a hydroxyl group also includes theanionic form (—O⁻), a salt or solvate thereof, as well as conventionalprotected forms of a hydroxyl group.

Alpha/Beta

The terms alpha and beta are used herein to indicate the relativeposition of substituent groups on rings. For the avoidance of doubt,their meaning is illustrated with the structure below:

wherein the bromo group is alpha to the chloro group, and the iodo groupis beta to the chloro group.

Isomers, Salts, Solvates, Protected Forms, and Prodrugs

Certain compounds may exist in one or more particular geometric,optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric,tautomeric, conformational, or anomeric forms, including but not limitedto, cis- and trans-forms; E- and Z-forms; c-, t-, and r-forms; endo- andexo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+)and (−) forms; keto-, enol-, and enolate-forms; syn- and anti-forms;synclinal- and anticlinal-forms; α- and β-forms; axial and equatorialforms; boat-, chair-, twist-, envelope-, and halfchair-forms; andcombinations thereof, hereinafter collectively referred to as “isomers”(or “isomeric forms”). Note that, except as discussed below fortautomeric forms, specifically excluded from the term “isomers”, as usedherein, are structural (or constitutional) isomers (i.e. isomers whichdiffer in the connections between atoms rather than merely by theposition of atoms in space). For example, a reference to a methoxygroup, —OCH₃, is not to be construed as a reference to its structuralisomer, a hydroxymethyl group, —CH₂OH. Similarly, a reference toortho-chlorophenyl is not to be construed as a reference to itsstructural isomer, meta-chlorophenyl. However, a reference to a class ofstructures may well include structurally isomeric forms falling withinthat class (e.g., C₁₋₇ alkyl includes n-propyl and iso-propyl; butylincludes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-,meta-, and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example,keto-, enol-, and enolate-forms, as in, for example, the followingtautomeric pairs: keto/enol (illustrated below), imine/enamine,amide/imino alcohol, amidine/amidine, nitroso/oxime,thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.

Note that specifically included in the term “isomer” are compounds withone or more isotopic substitutions. For example, H may be in anyisotopic form, including ¹H, ²H (D), and ³H (T); C may be in anyisotopic form, including ¹²C, ¹³C and ¹⁴C; O may be in any isotopicform, including ¹⁶O and ¹⁸O; and the like.

Unless otherwise specified, a reference to a particular compoundincludes all such isomeric forms, including (wholly or partially)racemic and other mixtures thereof. Methods for the preparation (e.g.asymmetric synthesis) and separation (e.g., fractional crystallisationand chromatographic means) of such isomeric forms are either known inthe art or are readily obtained by adapting the methods taught herein,or known methods, in a known manner.

Unless otherwise specified, a reference to a particular compound alsoincludes ionic, salt, solvate, and protected forms of thereof, forexample, as discussed below.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding salt of the active compound, for example, apharmaceutically-acceptable salt. Examples of pharmaceuticallyacceptable salts are discussed in Berge et al. J. Pharm. Sci., 66, 1-19(1977).

For example, if the compound is anionic, or has a functional group whichmay be anionic (e.g., —COOH may be —COO⁻), then a salt may be formedwith a suitable cation. Examples of suitable inorganic cations include,but are not limited to, alkali metal ions such as Na⁺ and K⁺, alkalineearth cations such as Ca²⁺ and Mg²⁺, and other cations such as Al³⁺.Examples of suitable organic cations include, but are not limited to,ammonium ion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺,NH₂R₂ ⁺, NHR₃ ⁺, NR₄ ⁺). Examples of some suitable substituted ammoniumions are those derived from: ethylamine, diethylamine,dicyclohexylamine, triethylamine, butylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine, benzylamine,phenylbenzylamine, choline, meglumine, and tromethamine, as well asamino acids, such as lysine and arginine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

If the compound is cationic, or has a functional group which may becationic (e.g., —NH₂ may be —NH₃ ⁺), then a salt may be formed with asuitable anion. Examples of suitable inorganic anions include, but arenot limited to, those derived from the following inorganic acids:hydrochloric, hydrobromic, hydroiodic, sulphuric, sulphurous, nitric,nitrous, phosphoric, and phosphorous. Examples of suitable organicanions include, but are not limited to, those derived from the followingorganic acids: acetic, propionic, succinic, glycolic, stearic, palmitic,lactic, malic, pamoic, tartaric, citric, gluconic, ascorbic, maleic,hydroxymaleic, phenylacetic, glutamic, aspartic, benzoic, cinnamic,pyruvic, salicyclic, sulfanilic, 2-acetyoxybenzoic, fumaric,phenylsulfonic, toluenesulfonic, methanesulfonic, ethanesulfonic, ethanedisulfonic, oxalic, pantothenic, isethionic, valeric, lactobionic, andgluconic. Examples of suitable polymeric anions include, but are notlimited to, those derived from the following polymeric acids: tannicacid, carboxymethyl cellulose.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding solvate of the active compound. The term “solvate” is usedherein in the conventional sense to refer to a complex of solute (e.g.active compound, salt of active compound) and solvent. If the solvent iswater, the solvate may be conveniently referred to as a hydrate, forexample, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.

It may be convenient or desirable to prepare, purify, and/or handle theactive compound in a chemically protected form. The term “chemicallyprotected form”, as used herein, pertains to a compound in which one ormore reactive functional groups are protected from undesirable chemicalreactions, that is, are in the form of a protected or protecting group(also known as a masked or masking group or a blocked or blockinggroup). By protecting a reactive functional group, reactions involvingother unprotected reactive functional groups can be performed, withoutaffecting the protected group; the protecting group may be removed,usually in a subsequent step, without substantially affecting theremainder of the molecule. See, for example, Protective Groups inOrganic Synthesis (T. Green and P. Wuts, Wiley, 1999).

For example, a hydroxy group may be protected as an ether (—OR) or anester (—OC(═O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl(diphenylmethyl), or trityl (triphenylmethyl)ether; a trimethylsilyl ort-butyldimethylsilyl ether; or an acetyl ester (—OC(═O)CH₃, —OAc).

For example, an aldehyde or ketone group may be protected as an acetalor ketal, respectively, in which the carbonyl group (>C═O) is convertedto a diether (>C(OR)₂), by reaction with, for example, a primaryalcohol. The aldehyde or ketone group is readily regenerated byhydrolysis using a large excess of water in the presence of acid. Forexample, an amine group may be protected, for example, as an amide or aurethane, for example, as: a methyl amide (—NHCO—CH₃); a benzyloxy amide(—NHCO—OCH₂C₆H₅, —NH—Cbz); as a t-butoxy amide (—NHCO—OC(CH₃)₃,—NH-Boc); a 2-biphenyl-2-propoxy amide (—NHCO—OC(CH₃)₂C₆H₄C₆H₅,—NH—Bpoc), as a 9-fluorenylmethoxy amide (—NH—Fmoc), as a6-nitroveratryloxy amide (—NH—Nvoc), as a 2-trimethylsilylethyloxy amide(—NH—Teoc), as a 2,2,2-trichloroethyloxy amide (—NH—Troc), as anallyloxy amide (—NH—Alloc), as a 2(-phenylsulphonyl)ethyloxy amide(—NH—Psec); or, in suitable cases, as an N-oxide (>NO.).

For example, a carboxylic acid group may be protected as an ester forexample, as: an C₁₋₇ alkyl ester (e.g. a methyl ester; a t-butyl ester);a C₁₋₇ haloalkyl ester (e.g., a C₁₋₇ trihaloalkyl ester); a triC₁₋₇alkylsilyl-C₁₋₇ alkyl ester; or a C₅₋₂₀ aryl-C₁₋₇ alkyl ester (e.g. abenzyl ester; a nitrobenzyl ester); or as an amide, for example, as amethyl amide. For example, a thiol group may be protected as a thioether(—SR), for example, as: a benzyl thioether; an acetamidomethyl ether(—S—CH₂NHC(═O)CH₃).

It may be convenient or desirable to prepare, purify, and/or handle theactive compound in the form of a prodrug. The term “prodrug”, as usedherein, pertains to a compound which, when metabolised (e.g. in vivo),yields the desired active compound. Typically, the prodrug is inactive,or less active than the active compound, but may provide advantageoushandling, administration, or metabolic properties. For example, someprodrugs are esters of the active compound (e.g. a physiologicallyacceptable metabolically labile ester). During metabolism, the estergroup (—C(═O)OR) is cleaved to yield the active drug. Such esters may beformed by esterification, for example, of any of the carboxylic acidgroups (—C(═O)OH) in the parent compound, with, where appropriate, priorprotection of any other reactive groups present in the parent compound,followed by deprotection if required. Examples of such metabolicallylabile esters include those wherein R is C₁₋₇ alkyl (e.g. -Me, -Et);C₁₋₇ aminoalkyl (e.g. aminoethyl; 2-(N,N-diethylamino)ethyl;2-(4-morpholino)ethyl); and acyloxy-C₁₋₇ alkyl (e.g. acyloxymethyl;acyloxyethyl; e.g. pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl;1-(1-methoxy-1-methyl)ethyl-carbonxyloxyethyl; 1-(benzoyloxy)ethyl;isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl;cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl;cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl;(4-tetrahydropyranyloxy) carbonyloxymethyl;1-(4-tetrahydropyranyloxy)carbonyloxyethyl;(4-tetrahydropyranyl)carbonyloxymethyl; and1-(4-tetrahydropyranyl)carbonyloxyethyl).

Also, some prodrugs are activated enzymatically to yield the activecompound, or a compound which, upon further chemical reaction, yieldsthe active compound. For example, the prodrug may be a sugar derivativeor other glycoside conjugate, or may be an amino acid ester derivative.

Selectivity

The selectivity of the compounds for inhibiting VEGFR3 over otherkinases, such as FAK and/or VEGFR² can be demonstrated by cellular assayresults (see, for example, the VEGFR3 and VEGFR² assays describedbelow).

FURTHER EMBODIMENTS

The following embodiments and preferences relate to both first andsecond aspects of the invention and may be combined with one another asappropriate.

A

In the second aspect, A is optionally substituted phenyl and can havethe structures:

where the R_(1B) group cannot be alpha the connection point to the restof the compound.

In these embodiments (i.e. when A is phenyl), it may be preferred thateither there are no R_(1B) substituents, or a single R_(1B) substituent.If there is a single R_(1B) substituent it is may be meta or para, sofurther preferred A groups include:

In some embodiments of the first aspect, A is an optionally substituted6 membered heteroaryl group. 6 membered heteroaryl groups include, butare not limited to: pyridyl, isoxazinyl, pyridazinyl, pyrimidinyl,pyrazinyl and triazinyl.

In these embodiments, it may be preferred that A is pyridyl, which canhave the structures:

In these embodiments, it is preferred that when R^(1A) is present R^(1C)is not an oxo (═O) group. Of these structures, A⁶ may be furtherpreferred.

In these embodiments (i.e. when A is 6 membered heteroaryl group), itmay be preferred that there are no R^(1C) substituents. Thus, when A ispyridyl and there are no R^(1C) groups, it may have the structures:

Of these structures A^(6A) may be further preferred.

In some embodiments of the first aspect, A is an optionally substituted5 membered heteroaryl group. 5 membered heteroaryl groups include, butare not limited to: pyrrolyl; furanyl; thiophenyl; oxazolyl; isoxazolyl;oxadiazolyl; oxatriazolyl; thiazolyl; isothiazolyl; imidazolyl;pyrazolyl; triazolyl and tetrazolyl.

In these embodiments, it may be preferred that A is pyrazolyl, which canhave the structures:

In these embodiments, it is preferred that R^(1C) is not an oxo (═O)group. Of these structures A¹⁶ and A¹⁸ may be further preferred.

In these embodiments (i.e. when A is a 5 membered heteroraryl group), itmay be preferred that there are no R^(1C) substituents. Thus, when A ispyrazolyl and there are no R^(1C) groups, it may have the structures:

Of these structures A^(19A) may be further preferred.

Thus particularly preferred structures for A include:

R^(1A)

In some embodiments where R^(1A) is CH(R^(C1))NHZ¹, Z¹ may be any oneof:

-   -   (i) H;    -   (ii) C₁₋₃ alkyl optionally substituted by OH, preferably Me, or        CH₂CH₂OH;    -   (iii) C(═O)OC₁₋₃ alkyl, preferably C(═O)OMe; and    -   (iv) C(═O)Me.

In some of these embodiments, Z¹ may be selected from H, CH₂CH₂OH andC(═O)Me. Thus, in these embodiments, R^(1A) is selected from: CH₂NH₂;CH(CH₃)NH₂; CH(C₂H₅)NH₂; CH₂NHCH₂CH₂OH; CH(CH₃)NHCH₂CH₂OH; andCH(C₂H₅)NHCH₂CH₂OH. In some embodiments where R^(1A) is CH(R^(C1))NHZ¹,R^(C1) may be selected from H and methyl. Thus, in these embodiments,R^(1A) is selected from: CH₂NHZ¹; and CH(CH₃)NHZ¹.

In some embodiments where R^(1A) is CH(R^(C1))NHZ¹, Z¹ may be selectedfrom H and CH₂CH₂OH and R^(C1) may be selected from H and methyl. Thus,in these embodiments, R^(1A) is selected from: CH₂NH₂; CH₂NHCH₂CH₂OH;CH(CH₃)NH₂; and CH(CH₃)NHCH₂CH₂OH.

In some embodiments where R^(1A) is XNHZ², Z² may be any one of:

-   -   (i) H;    -   (ii) C₁₋₃ alkyl optionally substituted by OH, preferably Me, or        CH₂CH₂OH;    -   (iii) C(═O)OC₁₋₃ alkyl, preferably C(═O)OMe; and    -   (iv) C(═O)Me.

In some embodiments where R^(1A) is XNHZ², Z² may be H. Thus, in theseembodiments, R^(1A) has the structures:

In some embodiments where R^(1A) is XNHZ², Z² may be C(═O)OMe. Thus, inthese embodiments, R^(1A) has the structures:

In some embodiments where R^(1A) is XNHZ², X may be selected from CMe₂,and cyclobutylidene. Thus, in these embodiments, R^(1A) has thestructures:

In some embodiments where R^(1A) is XNHZ², Z² may be selected from H andC(═O)OMe, and X may be selected from CMe₂, and cyclobutylidene. Thus, inthese embodiments, R^(1A) has the structures:

In some embodiments, R^(1A) is:

wherein R^(N1) is selected from H, C₁₋₄ alkyl (i.e. methyl, ethyl,prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl),C₃₋₄ cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) andC(═O)Me. In some of these embodiments, it may be preferred that R^(N1)is C(═O)Me. In others of these embodiments, it may be preferred thatR^(N1) is H, methyl or ethyl.

In some embodiments, R^(1A) is:

wherein R^(N2) is selected from H, C₁₋₄ alkyl (i.e. methyl, ethyl,prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl),C₃₋₄ cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) andC(═O)Me. In some of these embodiments, it may be preferred that R^(N2)is C(═O)Me. In others of these embodiments, it may be preferred thatR^(N2) is H, methyl or ethyl, more preferably H or methyl.

In some embodiments, R^(1A) is:

wherein R^(N3) is selected from H, C₁₋₄ alkyl (i.e. methyl, ethyl,prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl),C₃₋₄ cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) andC(═O)Me. In some of these embodiments, it may be preferred that R^(N3)is C(═O)Me. In others of these embodiments, it may be preferred thatR^(N3) is H, methyl or ethyl, more preferably H or methyl.

In some embodiments, R^(1A) is:

wherein R^(N4) is selected from H or methyl. In some of theseembodiments, it may be preferred that R^(N4) is H.

In some embodiments, R^(1A) is:

wherein R^(N5) is selected from H, C₁₋₄ alkyl (i.e. methyl, ethyl,prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl),C₃₋₄ cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) andC(═O)Me. In some of these embodiments, it may be preferred that R^(N5)is C(═O)Me. In others of these embodiments, it may be preferred thatR^(N5) is H, methyl or ethyl, more preferably H or methyl.

In some embodiments, R^(1A) is:

wherein R^(N6) is selected from H, C₁₋₄ alkyl (i.e. methyl, ethyl,prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl),C₃₋₄ cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) andC(═O)Me. In some of these embodiments, it may be preferred that R^(N6)is C(═O)Me. In others of these embodiments, it may be preferred thatR^(N6) is H, methyl or ethyl, more preferably H or methyl.

In some embodiments, R^(1A) is:

wherein R^(N7) and R^(N8) are both H or both methyl. In some of theseembodiments, it may be preferred that R^(N7) and R^(N8) are both H. Insome embodiments, R^(1A) is:

wherein R^(N9) is selected from H, C₁₋₄ alkyl (i.e. methyl, ethyl,prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl),C₃₋₄ cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) andC(═O)Me. In some of these embodiments, it may be preferred that R^(N9)is C(═O)Me. In others of these embodiments, it may be preferred thatR^(N9) is H, methyl or ethyl, more preferably H or methyl.

In some embodiments, R^(1A) is:

wherein R^(N10) is selected from H, C₁₋₄ alkyl (i.e. methyl, ethyl,prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl),C₃₋₄ cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) andC(═O)Me. In some of these embodiments, it may be preferred that R^(N10)is C(═O)Me. In others of these embodiments, it may be preferred thatR^(N10) is H, methyl or ethyl, more preferably H or methyl.

In some embodiments, R^(1A) is:

wherein R^(N11) is selected from H, C₁₋₄ alkyl (i.e. methyl, ethyl,prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl),C₃₋₄ cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) andC(═O)Me. In some of these embodiments, it may be preferred that R^(N11)is C(═O)Me. In others of these embodiments, it may be preferred thatR^(N11) is H, methyl or ethyl, more preferably H or methyl.

In some embodiments, R^(1A) is:

wherein R^(N12) is selected from H, C₁₋₄ alkyl (i.e. methyl, ethyl,prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl),C₃₋₄ cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) andC(═O)Me. In some of these embodiments, it may be preferred that R^(N12)is C(═O)Me. In others of these embodiments, it may be preferred thatR^(N12) is H, methyl or ethyl, more preferably H or methyl.

Particularly preferred R^(1A) groups include:

R_(1B) (Second Aspect)

In some embodiments, no R_(1B) substituents are present.

In some embodiments, R_(1B) is preferably C₁₋₃ alkyl and more preferablymethyl.

In some embodiments, a single R_(1B) substituent is present. It may beC₁₋₃ alkyl; CF₃; F; Cl; O—(C₁₋₃ alkyl); and CN. In some of theseembodiments, it is preferably F or C₁₋₃ alkyl, and more preferably F ormethyl.

R^(1C) (First Aspect)

In some embodiments, no R^(1C) substituents are present.

In some embodiments, R^(1C) is preferably C₁₋₃ alkyl and more preferablymethyl.

In some embodiments, a single R^(1C) substituent is present. It may beC₁₋₃ alkyl; CF₃; F; Cl; O—(C₁₋₃ alkyl); CN; and ═O. In some of theseembodiments, it is preferably C₁₋₃ alkyl, and more preferably methyl.

R²

In some embodiments, R² is H.

In some embodiments, R² is halo (i.e. F, Cl, Br, I). In some of theseembodiments, the halo group is either F or Cl.

In some embodiments, R² is C₁₋₄ alkyl (i.e. methyl, ethyl, prop-1-yl andprop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl). In some of theseembodiments, the C₁₋₄ alkyl group is methyl or ethyl, and methyl may bepreferred.

In some embodiments, R² is selected from CF₃ and CF₂H. In some of theseembodiments, R² is CF₃.

In some embodiments, R² is CN.

In some embodiments, R² is methoxy.

R³

In some embodiments, R³ is substituted phenyl, and therefore it has thestructure:

where R⁶, R⁷ and R⁸ are independently selected from H, F, methyl andCF₃. One of R^(4A) and R^(4B) is R⁴, and the other is selected from H,F, methyl and CF₃. In some of these embodiments, the group of R^(4A) andR^(4B) that is not R⁴, and R⁶, R⁷ and R⁸ are all H. In others of theseembodiments, one of the group of R^(4A) and R^(4B) that is not R⁴, R⁶,R⁷ and R⁸ is not H, and therefore is F, methyl or CF₃. The group that isnot H may preferably be R⁶ or R⁷.

In some embodiments, R³ is substituted phenyl, R^(4B), R⁶, R⁷ and R⁸ areall H, and R^(4A) is R⁴.

In some embodiments, R³ is a substituted 6 membered heteroaryl group,where the heteroaryl ring system contains 1 or 2 N heteroatoms. In theseembodiments, it may be preferred that R³ is pyridyl, which can have thestructures:

where R⁶, R⁷ and R⁸ (if present) are independently selected from H, F,methyl and CF₃. One of R^(4A) and R^(4B) (if present) is R⁴, and theother is selected from H, F, methyl and CF₃. Of these structures, R^(3d)and R^(3e) may be preferred. In some of these embodiments, the group ofR^(4A) and R^(4B) that is not R⁴, and R⁶, R⁷ and R⁸ (if present) are allH. In others of these embodiments, one of the group of R^(4A) and R^(4B)that is not R⁴, R⁶, R⁷ and R⁸ (if present) is not H, and therefore is F,methyl or CF₃. In some embodiments, it may be preferred that a Fsubstituent is not alpha to a ring nitrogen atom.

R⁴

In some embodiments R⁴ is alpha to the —C₂H₄— group.

In some embodiments R⁴ is beta to the —C₂H₄— group.

In some embodiments, R^(N13) is H.

In other embodiments, R^(N13) is Me.

In some embodiments, Z³ is H.

In other embodiments, Z³ is Me.

In other embodiments, Z³ is OMe.

In some embodiments of the present invention the compounds of formula(I) are of formula (Ia) or isomers, salts, solvates, protected forms orprodrugs thereof wherein:

A is an optionally substituted 5 or 6 membered heteroaryl group linkedto the NH group through an aromatic ring carbon atom, in which theheteroaryl ring system contains 1 or 2 N atoms, and;

A may bear a substituent R^(1A) which is not alpha to the NH group andmay optionally further bear a substituent R^(1C) which are not alpha tothe NH group, where R^(1A) is selected from:

-   -   (i) CH(R^(C1))NHZ¹, where R^(C1) is selected from C₁₋₂ alkyl and        Z¹ is selected from H and C₁₋₃ alkyl optionally substituted by        OH;    -   (ii) XNHZ², where X is cyclobutylidene, and Z² is C(═O)OC₁₋₃        alkyl;    -   (iii) a group selected from:

-   -   wherein:        -   R^(N2) is selected from H and C₁₋₄ alkyl;        -   R^(N6) is H;    -   and where R^(1C) is C₁₋₃ alkyl;    -   R² is selected from C₁₋₄ alkyl and CF₃;    -   R³ is substituted phenyl, where R³ bears a substituent R⁴ alpha        to the —C₂H₄— group, and may additionally bear a further        substituent F; and    -   R⁴ is —CH₂—C(O)N(R^(N13))Z³, where R^(N13) is H; and Z³ is H.

In some embodiments of the present invention the compounds of formula(I) are of formula (Ib) or isomers, salts, solvates, protected forms orprodrugs thereof wherein:

A is an optionally substituted 5 or 6 membered heteroaryl group linkedto the NH group through an aromatic ring carbon atom, in which theheteroaryl ring system contains 1 or 2 N atoms, and;

A may bear a substituent R^(1A) which is not alpha to the NH group andmay optionally further bear a substituent R^(1C) which are not alpha tothe NH group, where R^(1A) is R^(1A2):

-   -   wherein:        -   R^(N2) is selected from H and C₁₋₄ alkyl;    -   and where R^(1C) is C₁₋₃ alkyl;    -   R² is selected from C₁₋₄ alkyl;    -   R³ is substituted phenyl, where R³ bears a substituent R⁴ alpha        to the —C₂H₄— group; and    -   R⁴ is —CH₂—C(O)N(R^(N13))Z³, where R^(N13) is H; and Z³ is H.

In some embodiments of the present invention the compounds of formula(I) are of formula (Ic) or isomers, salts, solvates, protected forms orprodrugs thereof wherein:

wherein R^(1A) is selected from:

-   -   (i) CH(R^(C1))NHZ¹, where R^(C1) is selected from H and methyl        and Z¹ is selected from H and CH₂CH₂OH;    -   (ii) XNHZ², where X is selected from cyclobutylidene and        oxetanylidine and Z² is selected from H and C(═O)OMe;    -   (iii) a group selected from R^(1A1), R^(1A2), R^(1A6) and        R^(1A11):

-   -   wherein:        -   R^(N1) is selected from H and Me;        -   R^(N2) is selected from H and Me;        -   R^(N6) is selected from H and Me; and        -   R^(N12) is selected from H and Me;    -   and where there may be a single R^(1C) group which is methyl;    -   R² is selected from H, methyl and CF₃;    -   R³ is:

where R⁵, R⁶ and R⁷ are independently selected from H, F, methyl andCF₃, and only one of them is not H; and

-   -   R⁴ is —CH₂—C(O)NH₂.

In some embodiments of the present invention the compounds of formula(II) are of formula (IIa) or isomers, salts, solvates, protected formsor prodrugs thereof wherein:

A is substituted phenyl;

A may bear a substituent R^(1A) which is not alpha to the NH group andmay optionally further bear a substituent R_(1B) which is not alpha tothe NH group, where R^(1A) is selected from:

-   -   (i) CH(R^(C1))NHZ¹, where R^(C1) is selected from H and C₁₋₂        alkyl and Z¹ is selected from H, C₁₋₃ alkyl optionally        substituted by OH and C(═O)Me;    -   (ii) XNHZ², where X is selected from cyclobutylidene and        oxetanylidine and Z² is selected from H and C(═O)OC₁₋₃ alkyl;    -   (iii) a group selected from:

-   -   wherein:        -   R^(N1) is H;        -   R^(N2) is selected from H and C₁₋₄ alkyl;        -   R^(N6) is H;        -   R^(N11) is H; and        -   R^(N12) is H;    -   and where each R_(1B) is independently selected from:    -   (i) C₁₋₃ alkyl;    -   (iii) F;    -   R² is selected from H, halo, C₁₋₄ alkyl, CF₃ and methoxy;    -   R³ is substituted phenyl, where R³ bears a substituent R⁴ alpha        to the —C₂H₄— group, and may additionally bear a further        substituent selected from F, methyl and CF₃; and    -   R⁴ is —CH₂—C(O)N(R^(N13))Z³, where R^(N13) is H; and Z³ is H.

In some embodiments of the present invention the compounds of formula(II) are of formula (IIb) or isomers, salts, solvates, protected formsor prodrugs thereof wherein:

A is substituted phenyl;

A may bear a substituent R^(1A) which is not alpha to the NH group andmay optionally further bear a substituent R_(1B) which is not alpha tothe NH group, where R^(1A) is selected from:

-   -   (i) CH(R^(C1))NHZ¹, where R^(C1) is selected from H and C₁₋₂        alkyl and Z¹ is selected from H and C₁₋₃ alkyl optionally        substituted by OH;    -   (ii) XNHZ², where X is oxetanylidine and Z² is H;    -   (iii) a group selected from:

-   -   wherein:        -   R^(N1) is H;        -   R^(N2) is selected from H and C₁₋₄ alkyl;        -   R^(N6) is H;        -   R^(N11) is H; and        -   R^(N12) is H;    -   and where each R_(1B) is C₁₋₃ alkyl;    -   R² is selected from halo, C₁₋₄ alkyl, CF₃ and methoxy;    -   R³ is substituted phenyl, where R³ bears a substituent R⁴ alpha        to the —C₂H₄— group, and may additionally bear a further        substituent selected from methyl and CF₃; and    -   R⁴ is —CH₂—C(O)N(R^(N13))Z³, where R^(N13) is H; and Z³ is H.

In some embodiments of the present invention the compounds of formula(II) are of formula (IIc) or isomers, salts, solvates, protected formsor prodrugs thereof wherein: A is:

wherein R^(1A) is selected from:

-   -   (i) CH(R^(C1))NHZ¹, where FP is selected from H and methyl and        Z¹ is selected from H and CH₂CH₂OH;    -   (ii) XNHZ², where X is selected from cyclobutylidene and        oxetanylidine and Z² is selected from H and C(═O)OMe;    -   (iii) a group selected from R^(1A1), R^(1A2), R^(1A6) and        R^(1A11):

-   -   wherein:        -   R^(N1) is selected from H and Me;        -   R^(N2) is selected from H and Me;        -   R^(N6) is selected from H and Me; and        -   R^(N12) is selected from H and Me;    -   and where there may be a single R_(1B) group which is selected        from F and methyl;    -   R² is selected from H, methyl and CF₃;    -   R³ is:

where R5, R⁶ and R⁷ are independently selected from H, F, methyl andCF₃, and only one of them is not H; and

-   -   R⁴ is —CH₂—C(O)NH₂.

The preferences expressed in relation to compounds of formulae I and IIalso apply to compounds of formulae Ia, Ib, Ic, IIa, IIb and IIc, whereappropriate.

Embodiments of the inventions are compounds of the examples, includingcompounds 1 to 41. Embodiments of particular interest include compounds5, 6, 14, 16, 24, 28, 30 and 31.

General Synthesis Methods

The compounds of the invention can be prepared by employing thefollowing general methods and using procedures described in detail inthe experimental section. The reaction conditions referred to areillustrative and non-limiting.

The process for the preparation of a compound of formula (I) or formula(II) or isomers, salts, solvates or prodrug thereof comprises reacting acompound of formula F1

with a compound of formula A-NH₂ to displace the group L¹ and with acompound of formula HC≡R³ to displace the group L², orwith a compound of formula HC≡R³ to displace the group L² and with acompound of formula A-NH₂ to displace the group L¹,wherein A, R² and R³ are as defined in formula (I) or (II) above and L¹and L² are leaving groups.

It will be appreciated that the compound of formula A-NH₂ and thecompound of formula HC≡R³ can be reacted with the compound of formula F1separately or sequentially in any order or simultaneously.

The leaving groups L¹ and L² may be any suitable leaving groups, such asa halogen atom (F, Cl, Br, I), —SR or —SO₂R where R is a C₁₋₄ straightchain or branched alkyl group. In some embodiments, L¹ and L² may be thesame or different and may be selected from the group consisting of Cl,Br, I, SMe, SO₂Me.

Compounds of formulae I and II, as described above, can be prepared bysynthetic strategies outlined below, wherein the definitions aboveapply:

Compounds of formula F1 may be reacted with substituted commercial orsynthetic amino substituted compounds of formula F2 (as prepared inscheme C to N) to form intermediates of formula F₃ where L¹ and L² maybe the same or different and include Cl, Br, I, SMe, SO₂Me. Compounds ofthe formula F1 may be prepared where L¹ and L² are different to allowregioselective substitution or when L¹=L² suitable reaction conditionscan be employed (choice of solvent, reaction temperature, addition of aLewis acid, for example ZnCl₂ in Et₂O) to allow L¹ to be selectivelydisplaced over L². Where regiochemical mixtures and di-substitution areobtained the regioisomers may be separated by chromatography.

Compounds of the formula F1 where L¹=L² are either commerciallyavailable, for example 2,4-dichloro-5-(trifluoromethyl)pyrimidine,2,4-dichloro-5-fluoropyrimidine, 2,4,5-trichloropyrimidine,2,4-dichloro-5-bromopyrimidine, 2,4-dichloro-5-iodopyrimidine,2,4-dichloro-5-methylpyrimidine, 2,4-dichloro-5-cyanopyrimidine or maybe prepared readily from commercial starting materials. Where R^(2=CF) ₃and differentiation of L¹ and L² is desirable, the method outlined inscheme B may be employed.

Commercially available 2,4-dichloro-5-(trifluoromethyl)pyrimidine (G1)can be selectively reacted with sodium thiomethoxide in the presence ofzinc(II) chloride to give2-thiomethyl-4-chloro-5-(trifluoromethyl)pyrimidine (G2).2-Thiomethyl-4-chloro-5-(trifluoromethyl)pyrimidine (G2) can be furtherreacted, for example by conversion to2-thiomethyl-4-iodo-5-(trifluoromethyl)pyrimidine (G3) under Finkelsteinconditions and/or by oxidation with m-CPBA to give the correspondingsulfone if further differentiation of the 2 and 4-position is requiredor if additional activation is desirable. Examples of commerciallyavailable amino compounds of the formula F2 include, but are not limitedto those depicted in table 1.

TABLE 1

It will be appreciated that compounds of the formula F2, both commercialand synthetic, can be further modified either prior or post coupling topyrimidines of the formula F1 via an extensive range of chemistriesincluding, but not limited to hydrolysis, alkylation, acylation,electrophilic halogenation and Mitsunobu coupling.

In addition to commercially available amino compounds of the formula F2,numerous analogous nitro containing compounds are also commerciallyavailable including, but not limited to those depicted in table 2.

TABLE 2

It will be appreciated that such compounds can be reduced under suitableconditions, for example in the presence of palladium under an atmosphereof hydrogen, to give amino compounds of the formula F2.

Synthetic amino compounds of the invention may be prepared via a rangeof procedures. It will be appreciated that heterocyclic analogues mayalso be prepared by analogous methods to those outlined below viasubstitution of phenyl containing starting materials with suitableheteroaromatic systems.

Commercially available 1-(4-nitrophenyl)piperazine (G4), or a saltthereof, can be reacted with Boc anhydride to give tert-butyl4-(4-nitrophenyl)piperazine-1-carboxylate (G5). Subsequent reduction viahydrogenation in the presence of a catalyst, for example palladium oncharcoal, gives the corresponding aniline, tert-butyl4-(4-aminophenyl)piperazine-1-carboxylate (G6).

tert-Butyl 4-(3-aminophenyl)piperazine-1-carboxylate (G9) can beprepared by coupling of commercially available tert-butylpiperazine-1-carboxylate (G7) and compounds of the formula F4, whereL³=I or Br, in a Buchwald type reaction to give tert-butyl4-(3-nitrophenyl)piperazine-1-carboxylate (G8). Reduction with hydrogenin the presence of a catalyst, for example palladium on charcoal, givestert-butyl 4-(3-aminophenyl)piperazine-1-carboxylate (G9).

The corresponding 4-piperidine analogues of G6 can be prepared by asequence of reactions starting with the conversion of commerciallyavailable tert-butyl 4-oxopiperidine-1-carboxylate (G10) to vinyltriflate G11. Coupling of G11 in a Suzuki type reaction with(4-nitrophenyl)boronic acid (G12) gives tetrahydropyridine G13.Subsequent reduction via hydrogenation in the presence of a catalyst,for example palladium on charcoal, gives tert-butyl4-(4-aminophenyl)piperidine-1-carboxylate (G14).

The corresponding 4-(3-aminophenyl)piperidine analogue of G9 can beprepared by a sequence of reactions starting with the conversion ofcommercially available tert-butyl 4-oxopiperidine-1-carboxylate (G10) tovinyl triflate G11. Coupling of G11 in a Suzuki type reaction with(3-nitrophenyl)boronic acid (G15) gives tetrahydropyridine G16.Subsequent reduction via hydrogenation in the presence of a catalyst,for example palladium on charcoal, gives tert-butyl4-(3-aminophenyl)piperidine-1-carboxylate (G17).

The 3-(4-aminophenyl)piperidine regioisomers of G14 can be prepared byreaction of commercially available compounds of the formula F5, whereL³=I or Br, with pyridin-3-ylboronic acid (G18) in a Suzuki typereaction to form 3-(4-nitrophenyl)pyridine (G19). Reduction of G19 withhydrogen in the presence of a catalyst, for example platinum oxide,gives 4-(piperidin-3-yl)aniline (G20) which may be protected using Bocanhydride to give tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate(G21).

The 2-(4-aminophenyl)piperidine regioisomer of G14 can be prepared byreaction of commercially available compounds of the formula F5, whereL³=I or Br, with pyridin-2-ylboronic acid (G22) in a Suzuki typereaction to form 2-(4-nitrophenyl)pyridine (G23). Reduction of G23 withhydrogen in the presence of a catalyst, for example platinum oxide,gives 4-(piperidin-2-yl)aniline (G24) which may be protected using Bocanhydride to give t ert-butyl 2-(4-aminophenyl)piperidine-1-carboxylate(G25).

Commercially available tert-butyl 3-oxopyrrolidine-1-carboxylate (G26)can be converted to a mixture of vinyl triflates G27 and G28 in thepresence of a triflamide and a suitable base, for example NaHMDS.Coupling of the mixture with (4-nitrophenyl)boronic acid (G12) underSuzuki conditions gives dihydropyrroles G29 and G30. Reduction of thismixture using hydrogen in the presence of a catalyst, for example 10%palladium on charcoal, gives tert-butyl3-(4-aminophenyl)pyrrolidine-1-carboxylate (G31).

A metal/silyl mediated coupling of commercially available tert-butyl3-iodoazetidine-1-carboxylate (G32) and 4-iodo-nitrobenzene (G33) givestert-butyl 3-(4-nitrophenyl)azetidine-1-carboxylate (G34). Subsequentreduction via hydrogenation in the presence of a catalyst, for examplepalladium on charcoal, gives the tert-butyl3-(4-aminophenyl)azetidine-1-carboxylate (G35).

tert-Butyl (1-(4-aminophenyl)piperidin-4-yl)carbamate (G39) can beprepared by nucleophilic aromatic substitution of commercially availabletert-butyl piperidin-4-ylcarbamate (G36) and 1-fluoro-4-nitrobenzene(G37) under thermal conditions to give tert-butyl(1-(4-nitrophenyl)piperidin-4-yl)carbamate (G38). Reduction of G38 withhydrogen in the presence of a catalyst, for example 10% palladium oncharcoal, gives tert-butyl (1-(4-aminophenyl)piperidin-4-yl)carbamate(G39).

Commercially available 2-bromo-1-(4-nitrophenyl)ethanone (G40) can bereduced and cyclised to give epoxide G41. Opening of the epoxide withtosylamide followed by cyclisation with (2-bromoethyl)diphenylsulfoniumtrifluoromethanesulfonate gives morpholine G43. Cleavage of thesulphonamide and subsequent re-protection with Boc anhydride givescarbamate G45. Reduction using hydrazine in the presence of iron(III)chloride gives tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate(G46).

tert-Butyl 4-(4-aminobenzyl)piperazine-1-carboxylate (G49) can beprepared by the nucleophilic displacement of commercially available1-(bromomethyl)-4-nitrobenzene (G47) with tert-butylpiperazine-1-carboxylate (G7) to give tert-butyl4-(4-nitrobenzyl)piperazine-1-carboxylate (G48). Subsequent reductionwith hydrogen in the presence of a catalyst, for example 10% palladiumon charcoal, gives tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate(G49).

Compounds of the formula F2 containing benzylamine or substitutedbenzylamines may either be purchased with suitable protecting groups inplace to allow selective reaction at the aniline or synthesised using anEllman type procedure as out lined in scheme N.

Carbonyl compounds of the formula F6 can be reacted with2-methylpropane-2-sulfinamide (G50) to give compounds of the formula F7.Compounds of the formula F7 can be reacted with anions prepared fromsuitably protected amino compounds, for exampleN-(4-bromophenyl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine (G51)treated with n-butyllithium, to give compounds of the formula F8.Hydrolysis of compounds of the formula F8 under acidic conditions, forexample using aqueous hydrochloric acid, gives compounds of the formulaF9. Where necessary, compounds of the formula F9 can be furtherprotected to facilitate regiospecific reactivity. It will be appreciatedthat Q¹ and Q² may be the same or different and may be fused together toform a ring structure, for example as in cyclobutanone—Substituents Q¹and Q² form either R^(C1) or part of X in compounds of formula I. Itwill also be appreciated that anions of suitably protected aminoheterocycles may be added to compounds of the formula F7 to giveheterocyclic analogues of compounds of the formula F9.

Where compounds are required where R³ is aryl or substituted arylcompounds of the formula F13 may be prepared as outlined in scheme O.

Compounds of the formulae F10 and F11 where R¹⁰ are independently H, F,Me or CF₃; Q³ may be OH, O-alkyl, NH₂ or substituted N and X=Cl, Br orI, are either commercially available or may be prepared synthetically.It will be appreciated that for compounds of the formula F10 and F11that the nature of Q³ can be readily changed. For example, a carboxylicacid may be converted to a corresponding ester or amide as required andconversely esters and amides can be hydrolysed to give carboxylic acids.Halogenation, for example using N-bromosuccinimide, of compounds of theformula F10 gives compounds of the formula F11, Compounds of the formulaF11 may be reacted under Sonagashira type coupling conditions to giveacetylenes of the formula F12 where R⁹=TMS, TES or C(CH₃)₂OH. R⁹ maythen be removed to generate compounds of the formula F13. When R⁹=TMS orTES potassium carbonate or tetra-n-butyl ammonium fluoride may beemployed to induce this transformation. When R⁹=C(CH₃)₂OH, sodiumhydride in refluxing toluene may be used.

Alternatively, when compounds in which R³=heteroaryl are desired,heteroaryl analogues of F13 may be prepared as outlined in Schemes P, Qand R.

For pyrazine containing analogues, 2,3-di-chloropyrazine (G52) can bereacted with ethyl acetate in the presence of LiHMDS to give ester G53.Coupling of ester G53 with TMS acetylene under Sonagashira conditionsgives ethyl 2-(3-((trimethylsilyl)ethynyl)pyrazin-2-yl)acetate (G54).Removal of the trimethylsilyl group using TBAF gives ethyl2-(3-ethynylpyrazin-2-yl)acetate (G55).

For pyrimidine analogues, diethyl succinate (G56) and ethyl formate(G57) can be condensed to give aldehyde G58 in the presence of sodiummetal. Cyclisation using thiourea gives4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine (G59). Desulfurisation usingRaney-nickel gives pyrimidone G60, which can be converted to 4-chloropyrimidine G61 using phosphorous oxychloride. Coupling of compound G61with TES-acetylene under Sonagashira conditions, followed by removal ofthe triethylsilyl group using TBAF gives ethyl2-(4-ethynylpyrimidin-5-yl)acetate (G63). It will be appreciated thatthe regioisomeric pyrimidine can be accessed by analogous series ofreactions from the isomer of G59.

For 3-pyridyl acetates, 2-(pyridin-3-yl)acetonitrile (G64) can beoxidised to N-oxide G65. Chlorination with phosphorous oxychloride gives2-chloropyridine G66 which can be hydrolysed with sodium hydroxide toacetic acid G67. Ester formation using methanol gives 2-chloropyridineester G68. Coupling of compounds ester G68 with TES-acetylene underSonagashira conditions, followed by removal of the triethylsilyl groupusing TBAF gives methyl 2-(2-ethynylpyridin-3-yl)acetate (G70). It willbe appreciated that the other regioisomeric pyridine analogues can beprepared using an analogous sequence starting from other commerciallyavailable pyridyl acetates.

Pyrimidines of the formula F₃ may be reacted with terminal acetylenes ofthe formula F13 to give acetylenes of the formula F14 in a Sonagashiratype coupling. The acetylene in compounds of the formula F14 may bereduced to an alkane of the formula F15 using hydrogen gas in thepresence of a transition metal catalyst. The exact choice of catalystand conditions employed is dependent on the nature of R². For example,where R²=F, CF₃, methyl or methoxy, 10% Pd/C may be used, where R²=Cl,platinum oxide is employed. Functional group manipulation may be carriedon compounds of the formula F15 if necessary. For example, compounds ofthe formula F15 where Q³=O-alkyl (i.e. esters) may then be deprotectedto give carboxylic acids of the formula F15 where Q³=OH. In esters whereQ³=OMe, lithium hydroxide solutions may be employed. Where Q³=Ot—Bu,acidic solutions, for example trifluoroacetic acid in dichloromethanemay be used to facilitate hydrolysis. It will be appreciated that underacidic conditions Boc protecting groups in A will also be cleaved.

Compounds of the formula F15 where Q³=OH may then be converted to amidesand substituted amides as described in formula (I) using a suitablechoice of amine in the presence of a coupling agents for exampleEDCl.HCl or HATU.

It will be appreciated that heteroaromatic analogues of compounds of theformula F13 (as described in schemes P, Q and R) may be coupled in ananalogous manner to that described in scheme S and then furtherelaborated to amides as described above. Compounds of the formula F15,in which Q³=an amide or substituted amide may then be further modifiedby derivitisation of amine functionality present in A. For example,compounds of the formula F15 where A was prepared as described inschemes C to M, in which a tert-butyl carbamate is present, may behydrolysed in the presence of mild acid, for example trifluoroaceticacid, to give the parent amine. The amine functionality maybe furtherderivatised by reductive alkylation with formaldehyde in the presence ofsodium triacetoxyborohydride to give N-Me analogues; by reductivealkylation with acetaldehyde in the presence of sodiumtriacetoxyborohydride to give N-Et analogues or the N-acetyl analoguesmay be prepared by reaction with a suitable acylating agent, for exampleacetic anhydride.

Alternatively, a complementary approach to that described scheme S canbe employed, where R² is not CF₃, whereby pyrimidines of the formula F1are initially coupled to acetylenes of the formula F13 as detailed inscheme T.

Pyrimidines of the formula F1 may be coupled to acetylenes of theformula F13 to give acetylenes of the formula F16 in a Sonagashira typecoupling. Depending on the nature of R² these couplings may either beregioselective, or where mixtures are obtained, regioisomers may beseparated by chromatography. The acetylene in compounds of the formulaF16 may be reduced to an alkane of the formula F17 using hydrogen gas inthe presence of a transition metal catalyst. The exact choice ofcatalyst and conditions employed is dependent on the nature of R². Forexample, where R²=Me, 10% Pd/C may be used, where R²=Cl, platinum oxideis employed. The desired amide may already be present in compounds ofthe formula F13, or alternatively an ester may be used and subsequentlyderivatised as described above.

Compounds of the formula F17 may then be reacted with amino compounds ofthe formula F2, prepared as described above, to give compounds of theformula F15. Such couplings may either be mediated under acidicconditions, for example using trifluoroacetic acid in trifluoroethanolor using palladium catalysis in a Buchwald/Hartwig type coupling.Compounds of the formula 15 may then be further elaborated as desired asdescribed above.

Ketones of formula F18 where R¹¹ is an alkyl group or similar may besubstituted with amines to form compounds of formula F19. It will beappreciated that Q4 and Q5 may be the same such as H to form a primaryamine or different such as NHMe and may also be fused together to form aring structure, for example but not limited to azetidine, pyrrolidine,piperazine, morpholine and piperidine.

USE OF COMPOUNDS OF THE INVENTION

The present invention provides active compounds, specifically, active2,4,5-substituted pyrimidines.

The term “active”, as used herein, pertains to compounds which arecapable of inhibiting VEGFR3 activity, and specifically includes bothcompounds with intrinsic activity (drugs) as well as prodrugs of suchcompounds, which prodrugs may themselves exhibit little or no intrinsicactivity.

Assays which may be used in order to assess the VEGFR3 inhibitionoffered by a particular compound are described in the examples below.

The present invention further provides a method of inhibiting VEGFR3activity in a cell, comprising contacting said cell with an effectiveamount of an active compound, preferably in the form of apharmaceutically acceptable composition. Such a method may be practisedin vitro or in vivo.

The present invention further provides active compounds which inhibitVEGFR3 activity, as well as methods of inhibiting VEGFR3 activity,comprising contacting a cell with an effective amount of an activecompound, whether in vitro or in vivo.

Active compounds may also be used as part of an in vitro assay, forexample, in order to determine whether a candidate host is likely tobenefit from treatment with the compound in question.

The invention further provides active compounds for use in a method oftreatment of the human or animal body. Such a method may compriseadministering to such a subject a therapeutically-effective amount of anactive compound, preferably in the form of a pharmaceutical composition.

The term “treatment”, as used herein in the context of treating acondition, pertains generally to treatment and therapy, whether of ahuman or an animal (e.g. in veterinary applications), in which somedesired therapeutic effect is achieved, for example, the inhibition ofthe progress of the condition, and includes a reduction in the rate ofprogress, a halt in the rate of progress, amelioration of the condition,and cure of the condition. Treatment as a prophylactic measure (i.e.prophylaxis) is also included.

The term “therapeutically-effective amount” as used herein, pertains tothat amount of an active compound, or a material, composition or dosagefrom comprising an active compound, which is effective for producingsome desired therapeutic effect, commensurate with a reasonablebenefit/risk ratio.

Cancer

The present invention provides active compounds which are anticanceragents. One of ordinary skill in the art is readily able to determinewhether or not a candidate compound treats a cancerous condition for anyparticular cell type, either alone or in combination.

The invention provides the use of the active compounds for the treatmentof cancer in the human or animal body. The invention further providesactive compounds for use in a method of treatment of cancer in the humanor animal body. Such a use or method may comprise administering to sucha subject a therapeutically-effective amount of an active compound,preferably in the form of a pharmaceutical composition.

Examples of cancers include, but are not limited to, bone cancer, brainstem glioma, breast cancer, cancer of the adrenal gland, cancer of theanal region, cancer of the bladder, cancer of the endocrine system,cancer of the oesophagus, cancer of the head or neck, cancer of thekidney or ureter, cancer of the liver, cancer of the parathyroid gland,cancer of the penis, cancer of the small intestine, cancer of thethyroid gland, cancer of the urethra, carcinoma of the cervix, carcinomaof the endometrium, carcinoma of the fallopian tubes, carcinoma of therenal pelvis, carcinoma of the vagina, carcinoma of the vulva, chronicor acute leukemia, colon cancer, melanoma such as cutaneous orintraocular melanoma, haemetological malignancies, Hodgkin's disease,lung cancer, lymphocytic lymphomas, neoplasms of the central nervoussystem (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma,primary CNS lymphoma, prostate cancer, rectal cancer, renal cellcarcinoma, sarcoma of soft tissue, skin cancer, spinal axis tumors,stomach cancer and uterine cancer. In some embodiments, the cancer ismelanoma, breast cancer or head and neck cancer.

Any type of cell may be treated, including but not limited to, lung,gastrointestinal (including, e.g., bowel, colon), breast (mammary),ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas,brain, and skin.

Compounds of the present invention may also be useful in inhibitinglymphangiogenesis and/or suppressing lymph node metastasis. Compounds ofthe present invention may also be useful in preventing the spread ofcancer and in the prevention of metastisis.

In one embodiment there is provided the use of a compound of formula (I)or formula (II) or an isomer, salt, solvate, protected form or prodrugthereof to prevent the spread of cancer or prevent metastasis. There isalso provided a compound of formula (I) or formula (II) or an isomer,salt, solvate or prodrug thereof for use in a method for preventing thespread of cancer or preventing of metastasis.

In another embodiment there is provided an anti-cancer treatmentcomprising a compound of formula (I) or formula (II) or an isomer, salt,solvate or prodrug thereof and an anti-tumour agent.

The anti cancer treatment defined herein may be applied as a soletherapy or may involve, in addition to the compound of the invention,conventional surgery or radiotherapy or chemotherapy. Such chemotherapymay include one or more of the following categories of anti-tumouragents:—

(i) other antiproliferative/antineoplastic drugs and combinationsthereof, as used in medical oncology, such as alkylating agents (forexample cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chlorambucil, busulphan, temozolamide andnitrosoureas); antimetabolites (for example gemcitabine and antifolatessuch as fluoropyrimidines like 5 fluorouracil and tegafur, raltitrexed,methotrexate, cytosine arabinoside, and hydroxyurea); antitumourantibiotics (for example anthracyclines like adriamycin, bleomycin,doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and docetaxel (Taxotere) and polokinase inhibitors);and topoisomerase inhibitors (for example epipodophyllotoxins likeetoposide and teniposide, amsacrine, topotecan and camptothecin);

(ii) cytostatic agents such as antioestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of 5*-reductase suchas finasteride;

(iii) anti-invasion agents (for example c-Src kinase family inhibitorslike4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline(AZD0530; International Patent Application WO 01/94341),N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide(dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661 and4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline-3-carbonitrile(bosutinib, SKI-606; Cancer research (2003), 63(2), 375-81), andmetalloproteinase inhibitors like marimastat, inhibitors of urokinaseplasminogen activator receptor function or antibodies to Heparanase);

(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies(for example the anti erbB2 antibody trastuzumab [HerceptinT], theanti-EGFR antibody panitumumab, the anti erbB1 antibody cetuximab[Erbitux, C225] and any growth factor or growth factor receptorantibodies disclosed by Stern et al. Critical reviews inoncology/haematology, 2005, Vol. 54, pp 11-29); such inhibitors alsoinclude tyrosine kinase inhibitors, for example inhibitors of theepidermal growth factor family (for example EGFR family tyrosine kinaseinhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, ZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI 774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib,inhibitors of the hepatocyte growth factor family, inhibitors of theplatelet-derived growth factor family such as imatinib, inhibitors ofserine/threonine kinases (for example Ras/Raf signalling inhibitors suchas farnesyl transferase inhibitors, for example sorafenib (BAY43-9006)), inhibitors of cell signalling through MEK and/or AKT kinases,inhibitors of the hepatocyte growth factor family, c-kit inhibitors, ablkinase inhibitors, IGF receptor (insulin-like growth factor) kinaseinhibitors; aurora kinase inhibitors (for example AZD1152, PH739358,VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclindependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;

(v) antiangiogenic and antilymphangiogenic agents such as those whichinhibit the effects of vascular endothelial growth factor, [for examplethe anti vascular endothelial cell growth factor A (VEGFA) antibodybevacizumab (AvastinT), the anti vascular endothelial cell growth factorA (VEGFA) antibody ranibizumab, the anti-VEGF aptamer pegaptanib, theanti vascular endothelial growth factor receptor 3 (VEGFR3) antibodyIMC-3C5, the anti vascular endothelial cell growth factor C (VEGFC)antibody VGX-100, the anti vascular endothelial cell growth factor D(VEGFD) antibody VGX-200, the soluble form of the vascular endothelialgrowth factor receptor 3 (VEGFR3) VGX-300 and VEGF receptor tyrosinekinase inhibitors such as4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(vandetanib; ZD6474; Example 2 within WO 01/32651),4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline(cediranib; AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787;WO 98/35985), pazopanib (GW786034), axitinib (AG013736), sorafenib andsunitinib (SU11248; WO 01/60814), compounds such as those disclosed inInternational Patent Applications WO97/22596, WO 97/30035, WO 97/32856and WO 98/13354 and compounds that work by other mechanisms (for examplelinomide, inhibitors of integrin avb3 function and angiostatin)];

(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;

(viii) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene directed enzyme pro drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi drug resistance gene therapy; and

(ix) immunotherapy approaches, including for example ex vivo and in vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte macrophage colony stimulating factor, approaches to decreaseT cell anergy, approaches using transfected immune cells such ascytokine transfected dendritic cells, approaches using cytokinetransfected tumour cell lines and approaches using anti idiotypicantibodies

A combination of particular interest is with docetaxel. Other possiblecombinations of interest include with gemcitabine, cisplatin and thecamptothecin prodrug irinotecan.

Diseases Ameliorated by the Control and/or Inhibition ofLymphangiogenesis

The present invention provides active compounds which are useful inpreventing and/or treating diseases or conditions ameliorated by thecontrol and/or inhibition of lymphangiogenesis.

In one embodiment there is provided the use of a compound of formula (I)or formula (II) or an isomer, salt, solvate, protected form or prodrugthereof to inhibit, suppress or reduce lymphangiogenesis. There is alsoprovided a compound of formula (I) or formula (II) or an isomer, salt,solvate, protected form or prodrug thereof for use in the method ofinhibiting, suppressing or reducing lymphangiogenesis.

As discussed above, these diseases or conditions may include:

-   -   (a) eye diseases, for example corneal graft rejection and age        related macular degeneration;    -   (b) skin inflammations, such as skin lesions in patients with        psoriasis;    -   (c) rejection in renal transplantation.

Administration

The active compound or pharmaceutical composition comprising the activecompound may be administered to a subject by any convenient route ofadministration, whether systemically/peripherally or at the site ofdesired action, including but not limited to, oral (e.g. by ingestion);topical (including e.g. transdermal, intranasal, ocular, buccal, andsublingual); pulmonary (e.g. by inhalation or insufflation therapyusing, e.g. an aerosol, e.g. through mouth or nose); rectal; vaginal;parenteral, for example, by injection, including subcutaneous,intradermal, intramuscular, intravenous, intraarterial, intracardiac,intrathecal, intraspinal, intracapsular, subcapsular, intraorbital,intraperitoneal, intratracheal, subcuticular, intraarticular,subarachnoid, intravitreal and intrasternal; by implant of a depot, forexample, subcutaneously, intravitreal or intramuscularly. The subjectmay be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent(e.g. a guinea pig, a hamster, a rat, a mouse), murine (e.g. a mouse),canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a horse), aprimate, simian (e.g. a monkey or ape), a monkey (e.g. marmoset,baboon), an ape (e.g. gorilla, chimpanzee, orang-utan, gibbon), or ahuman.

Formulations

While it is possible for the active compound to be administered alone,it is preferable to present it as a pharmaceutical composition (e.g.formulation) comprising at least one active compound, as defined above,together with one or more pharmaceutically acceptable carriers,adjuvants, excipients, diluents, fillers, buffers, stabilisers,preservatives, lubricants, or other materials well known to thoseskilled in the art and optionally other therapeutic or prophylacticagents.

Thus, the present invention further provides pharmaceuticalcompositions, as defined above, and methods of making a pharmaceuticalcomposition comprising admixing at least one active compound, as definedabove, together with one or more pharmaceutically acceptable carriers,excipients, buffers, adjuvants, stabilisers, or other materials, asdescribed herein.

The term “pharmaceutically acceptable” as used herein pertains tocompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of a subject (e.g. human) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each carrier,excipient, etc. must also be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation.

Suitable carriers, excipients, etc. can be found in standardpharmaceutical texts, for example, Remington's Pharmaceutical Sciences,18th edition, Mack Publishing Company, Easton, Pa., 1990.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any methods well known in the art of pharmacy. Suchmethods include the step of bringing into association the activecompound with the carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association the active compound with liquidcarriers or finely divided solid carriers or both, and then if necessaryshaping the product.

Formulations may be in the form of liquids, solutions, suspensions,emulsions, elixirs, syrups, tablets, losenges, granules, powders,capsules, cachets, pills, ampoules, suppositories, pessaries, ointments,gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses,electuaries, or aerosols.

Formulations suitable for oral administration (e.g. by ingestion) may bepresented as discrete units such as capsules, cachets or tablets, eachcontaining a predetermined amount of the active compound; as a powder orgranules; as a solution or suspension in an aqueous or non-aqueousliquid; or as an oil-in-water liquid emulsion or a water-in-oil liquidemulsion; as a bolus; as an electuary; or as a paste.

A tablet may be made by conventional means, e.g., compression ormoulding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing in a suitable machine the activecompound in a free-flowing form such as a powder or granules, optionallymixed with one or more binders (e.g. povidone, gelatin, acacia,sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers ordiluents (e.g. lactose, microcrystalline cellulose, calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc, silica);disintegrants (e.g. sodium starch glycolate, cross-linked povidone,cross-linked sodium carboxymethyl cellulose); surface-active ordispersing or wetting agents (e.g. sodium lauryl sulfate); andpreservatives (e.g. methyl p-hydroxybenzoate, propyl p-hydroxybenzoate,sorbic acid). Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activecompound therein using, for example, hydroxypropylmethyl cellulose invarylng proportions to provide the desired release profile. Tablets mayoptionally be provided with an enteric coating, to provide release inparts of the gut other than the stomach.

Formulations suitable for topical administration (e.g. transdermal,intranasal, ocular, buccal, and sublingual) may be formulated as anointment, cream, suspension, lotion, powder, solution, past, gel, spray,aerosol, or oil. Alternatively, a formulation may comprise a patch or adressing such as a bandage or adhesive plaster impregnated with activecompounds and optionally one or more excipients or diluents.

Formulations suitable for topical administration in the mouth includelosenges comprising the active compound in a flavoured basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activecompound in an inert basis such as gelatin and glycerin, or sucrose andacacia; and mouthwashes comprising the active compound in a suitableliquid carrier.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active compound is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the active compound.

Formulations suitable for nasal administration, wherein the carrier is asolid, include a coarse powder having a particle size, for example, inthe range of about 20 to about 500 microns which is administered in themanner in which snuff is taken, i.e. by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid for administrationas, for example, nasal spray, nasal drops, or by aerosol administrationby nebuliser, include aqueous or oily solutions of the active compound.

Formulations suitable for administration by inhalation include thosepresented as an aerosol spray from a pressurised pack, with the use of asuitable propellant, such as dichlorodifluoromethane,trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, orother suitable gases.

Formulations suitable for topical administration via the skin includeointments, creams, and emulsions. When formulated in an ointment, theactive compound may optionally be employed with either a paraffinic or awater-miscible ointment base. Alternatively, the active compounds may beformulated in a cream with an oil-in-water cream base. If desired, theaqueous phase of the cream base may include, for example, at least about30% w/w of a polyhydric alcohol, i.e., an alcohol having two or morehydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol,sorbitol, glycerol and polyethylene glycol and mixtures thereof. Thetopical formulations may desirably include a compound which enhancesabsorption or penetration of the active compound through the skin orother affected areas. Examples of such dermal penetration enhancersinclude dimethylsulfoxide and related analogues.

When formulated as a topical emulsion, the oily phase may optionallycomprise merely an emulsifier (otherwise known as an emulgent), or itmay comprises a mixture of at least one emulsifier with a fat or an oilor with both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabiliser. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabiliser(s) make up theso-called emulsifying wax, and the wax together with the oil and/or fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Suitable emulgents and emulsion stabilisers include Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodiumlauryl sulphate. The choice of suitable oils or fats for the formulationis based on achieving the desired cosmetic properties, since thesolubility of the active compound in most oils likely to be used inpharmaceutical emulsion formulations may be very low. Thus the creamshould preferably be a non-greasy, non-staining and washable productwith suitable consistency to avoid leakage from tubes or othercontainers. Straight or branched chain, mono- or dibasic alkyl esterssuch as di-isoadipate, isocetyl stearate, propylene glycol diester ofcoconut fatty acids, isopropyl myristate, decyl oleate, isopropylpalmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branchedchain esters known as Crodamol CAP may be used, the last three beingpreferred esters. These may be used alone or in combination depending onthe properties required.

Alternatively, high melting point lipids such as white soft paraffinand/or liquid paraffin or other mineral oils can be used.

Formulations suitable for rectal administration may be presented as asuppository with a suitable base comprising, for example, cocoa butteror a salicylate.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active compound, such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration (e.g. by injection,including cutaneous, subcutaneous, intramuscular, intravenous andintradermal), include aqueous and non-aqueous isotonic, pyrogen-free,sterile injection solutions which may contain anti-oxidants, buffers,preservatives, stabilisers, bacteriostats, and solutes which render theformulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents, and liposomes or other microparticulatesystems which are designed to target the compound to blood components orone or more organs. Examples of suitable isotonic vehicles for use insuch formulations include Sodium Chloride Injection, Ringer's Solution,or Lactated Ringer's Injection. Typically, the concentration of theactive compound in the solution is from about 1 ng/mL to about 10 μg/mL,for example from about 10 ng/ml to about 1 μg/mL. The formulations maybe presented in unit-dose or multi-dose sealed containers, for example,ampoules and vials, and may be stored in a freeze-dried (lyophilised)condition requiring only the addition of the sterile liquid carrier, forexample water for injections, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules, and tablets. Formulations may be in the form ofliposomes or other microparticulate systems which are designed to targetthe active compound to blood components or one or more organs.

Dosage

It will be appreciated that appropriate dosages of the active compounds,and compositions comprising the active compounds, can vary from patientto patient. Determining the optimal dosage will generally involve thebalancing of the level of therapeutic benefit against any risk ordeleterious side effects of the treatments of the present invention. Theselected dosage level will depend on a variety of factors including, butnot limited to, the activity of the particular compound, the route ofadministration, the time of administration, the rate of excretion of thecompound, the duration of the treatment, other drugs, compounds, and/ormaterials used in combination, and the age, sex, weight, condition,general health, and prior medical history of the patient. The amount ofcompound and route of administration will ultimately be at thediscretion of the physician, although generally the dosage will be toachieve local concentrations at the site of action which achieve thedesired effect without causing substantial harmful or deleteriousside-effects.

Administration in vivo can be effected in one dose, continuously orintermittently (e.g. in divided doses at appropriate intervals)throughout the course of treatment. Methods of determining the mosteffective means and dosage of administration are well known to those ofskill in the art and will vary with the formulation used for therapy,the purpose of the therapy, the target cell being treated, and thesubject being treated. Single or multiple administrations can be carriedout with the dose level and pattern being selected by the treatingphysician.

In general, a suitable dose of the active compound is in the range ofabout 100 μg to about 250 mg per kilogram body weight of the subject perday. Where the active compound is a salt, an ester, prodrug, or thelike, the amount administered is calculated on the basis of the parentcompound and so the actual weight to be used is increasedproportionately.

EXAMPLES

The following examples are provided solely to illustrate the presentinvention and are not intended to limit the scope of the invention, asdescribed herein.

Acronyms

For convenience, many chemical moieties are represented using well knownabbreviations, including but not limited to, methyl (Me), ethyl (Et),n-propyl (nPr), iso-propyl (iPr), n-butyl (nBu), tert-butyl (tBu),n-hexyl (nHex), cyclohexyl (cHex), phenyl (Ph), methoxy (MeO), ethoxy(EtO), trimethylsilyl (TMS), tert-butyloxycarbonyl (Boc), and acetyl(Ac).

For convenience, many chemical compounds are represented using wellknown abbreviations, including but not limited to, methanol (MeOH),ethanol (EtOH), ether or diethyl ether (Et₂O), ethyl acetate (EtOAc),triethylamine (Et₃N), dichloromethane (methylene chloride, DCM),trifluoroacetic acid (TFA), trifluoroethanol (TFE), dimethylformamide(DMF), sodium sulphate (Na₂SO₄), tetrahydrofuran (THF),meta-chloroperbenzoic acid (mCPBA), hexamethyldisilazane sodium salt(NaHMDS), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), dimethylsulfoxide (DMSO), magnesium sulphate(MgSO₄), sodium hydrogen carbonate (NaHCO₃), tert-butanol (t-BuOH),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride salt(EDCl.HCl), tetra-n-butylammonium fluoride (TBAF),N,N-diisopropylethylamine (DIPEA), 1-hydroxybenzotriazole (HOBt),trans-dichlorobis(triphenylphosphine)palladium(II) (PdCl₂(PPh₃)₂),tris(dibenzylideneacetone) dipalladium(0) (Pd₂(dba)₃), tri-t-butylphosphonium tetrafluoroborate (t-Bu₃PH.BF₄),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos),triphenylphosphine (PPh₃) and 1,2-dichloroethane (DCE).

General Experimental Details

Unless otherwise stated the following generalisations apply.

In the examples below, in case the structures contain one or morestereogenic centres and the stereochemistry is depicted in the diagram,the respective stereochemistry is assigned in an arbitrary absoluteconfiguration. These structures depict single enantiomers as well asmixtures of enantiomers in all ratios, and/or mixtures ofdiastereoisomers in all ratios. ¹NMR spectra were recorded on either aBruker Avance DRX300 (300 MHz) or a Bruker Ultrashield plus (400 MHz).The multiplicity of a signal is designated by the followingabbreviations: s, singlet; d, doublet; dd, doublet of doublets; t,triplet; tt, triplet of triplets; td, triplet of doublets; q, quartet;br, broad; m, multiplet. All observed coupling constants, J, arereported in Hertz.

LC/MS data was generated using either an Agilent 6100 Series Single QuadLC/MS (LCMS-A) or Waters ZQ 3100 system (LCMS-B).

LCMS Method A (LCMS-A)

Instrument: Agilent 6100 Series Single Quad LC/MS

Agilent 1200 Series HPLC

Pump: 1200 Series G1311A Quaternary pump

Autosampler: 1200 Series G1329A Thermostatted Autosampler

Detector: 1200 Series G1314B Variable Wavelength Detector

LC Conditions:

Reverse Phase HPLC analysis

Column: Luna C8(2) 5μ 50×4.6 mm 100 A

Column temperature: 30° C.

Injection Volume: 5 μL

Solvent A: Water 0.1% Formic Acid

Solvent B: Acetonitrile 0.1% Formic Acid

Gradient: 5-100% B over 10 min

Detection: 254 nm or 214 nm

MS Conditions:

Ion Source Quadrupole

Ion Mode Multimode-ES

Drying gas temp: 300° C.

Vaporizer temperature: 200° C.

Capillary voltage (V): 2000 (positive)

Capillary voltage (V): 4000 (negative)

Scan Range: 100-1000

Step size: 0.1 sec

Acquisition time: 10 min

LCMS Method B (LCMS-B)

Instrument: Waters ZQ 3100-Mass Detector

Waters 2545-Pump

Waters SFO System Fluidics Organizer

Waters 2996 Diode Array Detector

Waters 2767 Sample Manager

LC Conditions:

Reverse Phase HPLC analysis

Column: XBridge™ C18 5 μm 4.6×100 mm

Injection Volume 10 μL

Solvent A: Water 0.1% Formic Acid

Solvent B: Acetonitrile 0.1% Formic Acid

Gradient: 10-100% B over 10 min

Flow rate: 1.5 ml/min

Detection: 100-600 nm

MS Conditions:

Ion Source Single-quadrupole

Ion Mode: ES positive

Source Temp: 150° C.

Desolvation Temp: 350° C.

Detection: Ion counting

Capillary (KV): 3.00

Cone (V): 30

Extractor (V):3

RF Lens (V): 0.1

Scan Range: 100-1000 Amu

Scan Time: 0.5 sec

Acquisition time: 10 min

Gas Flow: 100 L/hr

Desolvation: 650 L/hr

Semi-preparative HPLC separations were achieved using a Waters ZQ 3100system (HPLC)

Semi-Preparative HPLC (HPLC)

Instrument:

Waters ZQ 3100-Mass Detector

Waters 2545-Pump

Waters SFO System Fluidics Organizer

Waters 2996 Diode Array Detector

Waters 2767 Sample Manager

LC Conditions:

Reverse Phase HPLC analysis

Column: XBridge™ C18 5 μm, 19×50 mm

Injection Volume 500 μL

Solvent A: Water 0.1% Formic Acid

Solvent B: Acetonitrile 0.1% Formic Acid

Gradient: 25-100% B over 10 min

Flow rate: 19 ml/min

Detection: 100-600 nm

MS Conditions:

Ion Source: Single-quadrupole

Ion Mode: ES positive

Source Temp: 150° C.

Desolvation Temp: 350° C.

Detection: Ion counting

Capillary (KV): 3.00

Cone (V): 30

Extractor (V): 3

RF Lens (V): 0.1

Scan Range: 100-1000 Amu

Scan Time: 0.5 sec

Acquisition time: 10 min

Desolvation: 650 L/hr

Cone: 100 L/hr

LCMS Method C (LCMS-C)

Instrument: Finnigan LCG Advantage Max

Finnigan Surveyor LC Pump

Finnigan Surveyor Autosampler

Finnigan Surveyor PDA Detector

LC Conditions:

Reverse Phase HPLC analysis

Column: Gemini 3 μm C18 20×4.0 mm 110 A

Injection Volume: 10 μL

Solvent A: Water 0.1% Formic Acid

Solvent B: Acetonitrile 0.1% Formic Acid

Gradient: 10-100% B over 10 min

Detection: 100-600 nm

MS Conditions

Ion Source: Ion trap

Ion Mode: ES positive

Temp: 300° C.

Detection: Ion counting

Scan Range: 80-1000 Amu

Scan Time: 0.2 sec

Acquisition time: 10 min

Analytical thin-layer chromatography was performed on Merck silica gel60F254 aluminium-backed plates which were visualised using fluorescencequenching under UV light or using an acidic anisaldehyde or a basicpotassium permanganate dip. Flash chromatography was performed usingeither a Teledyne Isco CombiFlash Rf purification system using standardRediSep® cartridges or a Biotage Isolera purification system usingeither Grace, RediSep® or Biotage silica cartridges. Microwaveirradiation was achieved using a CEM Explorer SP Microwave Reactor. Allreactions carried out using microwave irradiation were stirred. Wherenecessary, anhydrous solvents were prepared using a Braun purificationsystem or purchased from Sigma-Aldrich.

Synthesis of Key Intermediates

Key Intermediate 1: Methyl 2-(2-ethynylphenyl)acetate (K1)

(a) Methyl 2-(2-iodophenyl)acetate (I1)

To a solution of 2-(2-iodophenyl)acetic acid (5.00 g, 19.1 mmol) in MeOH(150 mL) was added concentrated aqueous H₂SO₄ (250 μL) and the resultingmixture was stirred at 80° C. under nitrogen for 16 hours. The volatileswere removed by evaporation under reduced pressure and the residue wastaken up in EtOAc (100 mL). The resulting solution was washed with 10%aqueous NaHCO₃ (100 mL), dried (MgSO₄) and the volatiles evaporatedunder reduced pressure to give the title compound I1 as a clear liquid(5.20 g, 99%); ¹H NMR (400 MHz, CDCl₃) δ 7.85 (dd, J=7.9, 1.0 Hz, 1H),7.35-7.27 (m, 2H), 6.97 (m, 1H), 3.81 (s, 2H), 3.72 (s, 3H).

(b) Methyl 2-(2-((trimethylsilyl)ethynyl)phenyl)acetate (I2)

A mixture of methyl 2-(2-iodophenyl)acetate (I1) (4.65 g, 16.8 mmol),PdCl₂(PPh₃)₂ (295 mg, 421 μmol), CuI (80.0 mg, 421 μmol) and(trimethylsilyl)acetylene (2.80 mL, 20.2 mmol) in dry degassed THF (20mL) and Et₃N (20 mL) was stirred at room temperature for 16 hours. Thevolatiles were removed under reduced pressure to give a black residuewhich was adsorbed onto silica gel and purified using columnchromatography (0-5% EtOAc in petroleum benzine 40-60° C.) to give thetitle compound 12 as a light brown liquid (4.63 g, 99%); ¹H NMR (400MHz, CDCl₃) δ 7.48 (dd, J=7.5, 0.8 Hz, 1H), 7.32-7.14 (m, 3H), 3.84 (s,2H), 3.71 (s, 3H), 0.26 (s, 9H). LCMS-B: rt 6.64 min.

(c) Methyl 2-(2-ethynylphenyl)acetate (K1)

TBAF (1.0 M in THF; 28.5 mL, 28.5 mmol) was added to a solution ofmethyl 2-(2-((trimethylsilyl)ethynyl)phenyl)acetate (I2) (4.63 g, 19.0mmol) in DCM (200 mL) at 0° C. The solution was stirred at roomtemperature for 1 hour before washing with 10% aqueous NaHCO₃ (100 mL).The organic layer was dried (MgSO₄) before removing the volatiles invacuo to give a dark brown/black residue which was adsorbed onto silicagel and purified by column chromatography (Biotage Isolera, 0-10% EtOAcin petroleum benzine 40-60° C.) to give the title compound K1 as a redliquid (2.76 g, 83%); ¹H NMR (400 MHz, CDCl₃) δ 7.52 (dd, J=7.6, 1.1 Hz,1H), 7.43-7.16 (m, 3H), 3.88 (d, J=9.6 Hz, 2H), 3.77-3.52 (m, 3H), 3.28(s, 1H).

Key intermediate 2: Benzyl 4-(4-aminophenyl)piperazine-1-carboxylate(K2)

(a) Benzyl 4-(4-nitrophenyl)piperazine-1-carboxylate (I3)

Benzyl chloroformate (0.515 mL, 3.61 mmol) was added to a mixture of1-(4-nitrophenyl)piperazine hydrochloride (0.800 g, 3.28 mmol) and Et₃N(1.14 mL, 8.21 mmol) in THF (20 mL) at 0° C. The resulting mixture wasstirred at 0° C. for 1 hour then at room temperature for 2 hours. DCM(40 mL) was added and the organics were washed with saturated NaHCO₃ (40mL), water (40 mL) then dried over MgSO₄. The volatiles removed in vacuoto give the title compound I3 as a yellow solid (1.11 g, 99%); ¹H NMR(400 MHz, CDCl₃) δ 8.04-8.01 (m, 2H), 7.32-7.18 (m, obscured), 7.15 (s,1H), 6.72-6.69 (m, 2H), 5.06 (s, 2H), 3.62-3.54 (m, 4H), 3.37-3.26 (m,4H).

(b) Benzyl 4-(4-aminophenyl)piperazine-1-carboxylate (K2)

To a mixture of benzyl 4-(4-nitrophenyl)piperazine-1-carboxylate (I3)(1.11 g, 3.25 mmol) and CoCl₂ (0.844 g, 6.50 mmol) in MeOH (30 mL) wasadded NaBH₄ (1.23 g, 32.5 mmol) portion-wise at 0° C. Stirring wascontinued at 0° C. for 1 hour before aqueous 3 M HCl (10 mL) was added.The mixture was concentrated in vacuo to remove the MeOH and the aqueouslayer was extracted twice with diethyl ether. The aqueous layer wasbasified with 1 M aqueous NaOH and extracted twice with EtOAc. Thecombined organic extracts were dried (MgSO₄), concentrated in vacuo,then adsorbed onto silica gel and purified by silica gel columnchromatography (Biotage Isolera, 12 g SiO2 cartridge, 50-60% EtOAc inhexanes) to give the title compound K2 as a purple solid (397 mg, 39%);¹H NMR (400 MHz, CDCl₃) δ 7.40-7.29 (m, 5H), 6.83-6.78 (m, 2H),6.68-6.62 (m, 2H), 5.16 (s, 2H), 3.70-3.61 (m, 4H), 3.46 (s, 2H),3.10-2.86 (m, 4H). LCMS-A: rt 4.650 min; m/z 312.1 [M+H]⁺.

Key intermediate 3: tert-Butyl 4-(4-aminophenyl)piperazine-1-carboxylate(K3)

(a) tert-Butyl 4-(4-nitrophenyl)piperazine-1-carboxylate (I4)

To a solution of 1-(4-nitrophenyl)piperazine hydrochloride (5.00 g, 20.5mmol) in DCM (100 mL) was added Et₃N (7.15 mL, 51.3 mmol) and Bocanhydride (4.93 g, 22.6 mmol). The resulting solution was stirred atroom temperature for 20 hours before water (100 mL) and DCM (70 mL) wereadded. The aqueous layer was extracted with DCM (100 mL) then theorganics were combined, washed with brine (100 mL), dried (Na₂SO₄),filtered and concentrated in vacuo to give a yellow-orange residue. Theresidue was purified by silica gel column chromatography (BiotageIsolera, 120 g SiO₂ cartridge, 0-100% EtOAc in petroleum benzine 40-60°C.) to give the title compound I4 as a yellow solid (4.90 g, 78%); ¹HNMR (400 MHz, d₆-DMSO) δ 8.10-8.04 (m, 2H), 7.04-6.97 (m, 2H), 3.48 (m,8H), 1.42 (s, 9H). LCMS-A: rt 6.13 min; m/z 208.2 [(M-Boc)+2H]⁺.

(b) tert-Butyl 4-(4-aminophenyl)piperazine-1-carboxylate (K3)

A slurry of 10% Pd/C (0.500 g) in EtOAc (10 mL) was added to a solutionof tert-butyl 4-(4-nitrophenyl)piperazine-1-carboxylate (I4) (3.24 g,10.5 mmol) in EtOAc (90 mL) and the resulting suspension was stirredunder a hydrogen atmosphere for 42 hours at room temperature. Thecatalyst was removed by filtration through Celite, washing with EtOAc(7×10 mL), then the filtrate was evaporated to dryness to give the titlecompound K3 as a pale pink solid (2.92 g, 99%); ¹H NMR (400 MHz,d₆-DMSO) δ 6.72-6.66 (m, 2H), 6.52-6.45 (m, 2H), 4.60 (s, 2H), 3.44-3.39(m, 4H), 2.87-2.79 (m, 4H), 1.41 (s, 9H). LCMS-A: rt 4.40 min; m/z 278.2[M+H]⁺.

Key intermediate 4: tert-Butyl4-(5-aminopyridin-2-yl)piperidine-1-carboxylate (K4)

(a) tert-Butyl5-nitro-5′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate (I5)

To a mixture of N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacolester (1.52 g, 4.93 mmol), 2-bromo-5-nitropyridine (1.00 g, 4.93 mmol)and PdCl₂(PPh₃)₂ (173 mg, 0.246 mmol under nitrogen was added dioxane(30 mL) followed by 3 M aqueous Na₂CO₃ (4.93 mL, 14.8 mmol). Theresulting mixture was degassed with a stream of nitrogen for 10 minutesthen heated at reflux for 16 hours. On cooling, EtOAc (150 mL) was addedand the resulting mixture was washed with water (3×50 mL) and brine (50mL). The organics were dried (Na₂SO₄), filtered and concentrated underreduced pressure to give a brown solid that was purified by silica gelcolumn chromatography (Biotage Isolera, 40 g SiO₂ cartridge, 0-30% EtOAcin petroleum benzine 40-60° C.) to give the title compound I5 as ayellow solid (1.43 g, 95%); ¹H NMR (400 MHz, CDCl₃) δ 9.37 (dd, J=2.6,0.5 Hz, 1H), 8.43 (dd, J=8.8, 2.7 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H),6.95-6.83 (m, 1H), 4.20 (d, J=3.0 Hz, 2H), 3.67 (t, J=5.6 Hz, 2H),2.70-2.63 (m, 2H), 1.49 (s, 9H). LCMS-A: rt 6.140 min; m/z 304 [M−H]⁻.

(b) tert-Butyl 4-(5-aminopyridin-2-yl)piperidine-1-carboxylate (K4)

A slurry of 10% Pd/C (500 mg) in DMF (5 mL) was added to a solution oftert-butyl 5-nitro-5′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate(I5) (1.40, 4.59 mmol) in DMF (45 mL). The resulting mixture was stirredunder a hydrogen atmosphere for 16 hours at room temperature then EtOAc(100 mL) was added and the resulting solution filtered through a Celitepad, washing with EtOAc (150 mL). The filtrate was evaporated to drynessto give a residue that was purified by silica gel chromatography(Biotage Isolera, 40 g SiO₂ cartridge, 0-100% EtOAc in petroleum benzine40-60° C. and then 0-20% MeOH in EtOAc) to give the title compound K4 asa yellow oil (1.18 g, 93%); ¹H NMR (400 MHz, CDCl₃) δ 8.03 (dd, J=2.4,1.0 Hz, 1H), 7.00-6.87 (m, 2H), 4.22 (br. s, 2H), 3.59 (br. s, 2H),2.85-2.67 (m, 3H), 1.86 (m, 2H), 1.72-1.59 (m, 2H), 1.46 (s, 9H).LCMS-A: rt 4.416 min; m/z 278 [M+H]⁺. Key intermediate 5: tert-Butyl4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(K5)

2,4-Dichloro-5-(trifluoromethyl)pyrimidine (4.12 g, 19.0 mmol) wasstirred in a 1:1 t-BuOH:DCE mixture (400 mL) at room temperature. A 1.0M ZnCl₂ solution in Et₂O (21.7 mL, 21.7 mmol) was added cautiously andafter addition the reaction was stirred at room temperature for 10minutes. 1-Boc-4-(4-aminophenyl)piperidine (5.00 g, 18.1 mmol) was thenadded followed by Et₃N (6.05 mL, 43.4 mmol) and the resulting mixturewas stirred at room temperature overnight. The organic solvents wereevaporated and the resulting solid was suspended in water (500 mL). Thesuspension was sonicated for 30 minutes and then filtered. The filtercake was washed with water (2×100 mL) and dried under high vacuum togive the title compound K5 as a tan solid (8.11 g, 98%); ¹H NMR (400MHz, d₆-DMSO) δ 10.61 (s, 1H), 8.78 (s, 1H), 7.59 (d, J=8.4 Hz, 2H),7.23 (d, J=8.5 Hz, 2H), 4.07 (d, J=11.1 Hz, 2H), 2.80 (s, 2H), 2.65 (t,J=12.0 Hz, 1H), 1.74 (d, J=12.3 Hz, 2H), 1.42 (s, 11H). LCMS-A: rt 6.834min; m/z 457 [M+H]⁺.

Key intermediate 6:2-(2-(2-(2-Chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide (K6)

(a) 2-(2-Iodophenyl)acetamide (I6)

A solution of 2-iodophenylacetic acid (20.5 g, 78.2 mmol) in thionylchloride (70 mL) was stirred at 75° C. for 3 hours. The thionyl chloridewas removed in vacuo and the resulting residue was dissolved in DCM (100mL). Ammonium carbonate (15.03 g, 156.5 mmol) was added and theresulting mixture was stirred at 60° C. for 20 hours. The volatiles wereevaporated in vacuo, water (100 mL) was added and the resultingsuspension was sonicated for 1 minute, before filtering and washing thefilter cake with water then Et₂O. After air drying, the title compound16 was obtained as a light cream coloured solid (12.9 g, 63%); ¹H NMR(300 MHz, d₆-DMSO) δ 7.82 (d, J=8.3 Hz, 1H), 7.41 (brs s, 1H), 7.30-7.37(m, 2H), 6.95-7.01 (m, 2H), 3.55 (s, 2H). LCMS-B: rt 5.108 min; m/z 262[M+H] ⁺.

(b) 2-(2-((Trimethylsilyl)ethynyl)phenyl)acetamide (I7)

A mixture of 2-(2-iodophenyl)acetamide (I6) (12.91 g, 49.52 mmol), Et₃N(26 mL), ethynyltrimethylsilane (9.08 mL, 64.3 mmol), PdCl₂(PPh3)₂(0.347 g, 0.495 mmol) and CuI (0.188 g, 0.989 mmol) in DMF (44 mL) wasstirred under a nitrogen atmosphere at 50° C. for 3 hours. The volatileswere removed in vacuo and the resulting residue partitioned betweenEtOAc (100 mL) and water. The aqueous phase was extracted with EtOAc(3×50 mL), then the combined organic extracts were washed with water(3×70 mL), brine, dried (MgSO4), filtered and evaporated in vacuo togive the title compound I7 as a brown solid (11.4 g, 99%); ¹H NMR (300MHz, d₆-DMSO) δ 7.40 (d, J=7.5 Hz, 1H), 7.20-7.36 (m, 4H), 6.94 (brs,1H), 3.58 (s, 2H), 0.24 (s, 9H). LCMS-B: rt 6.884 min; m/z 232 [M+H] ⁺.

(c) 2-(2-Ethynylphenyl)acetamide (I8)

A 1.0 M solution of TBAF in THF (59.1 mL, 59.1 mmol) was slowly added toa cooled (5° C. water/ice bath) solution of2-(2-((trimethylsilyl)ethynyl)phenyl)acetamide (I7) (11.4 g, 49.3 mmol)in DCM (150 mL) and acetic acid (3.66 mL, 64.1 mmol). The mixture wasstirred at 5° C. for 1 hour before 10% aqueous NaHCO3 solution (150 mL)was added. The resulting mixture was extracted with DCM (3×50 mL) thenthe combined organics were dried (MgSO4), filtered and evaporated invacuo until approximately 15 mL of solvent remained. This solution wasdiluted with Et₂O (100 mL) and EtOAc (100 mL) resulting in the formationof a precipitate, which was filtered and dried to give 2.81 g of thetitle compound I8 as a brown solid. The remaining filtrate was adsorbedonto silica gel and purified using column chromatography (CombiFlash Rf,80 g SiO₂ Cartridge, 0-10% MeOH in DCM). An additional 2.62 g of thetitle compound I8 was isolated as a brown solid (combined total 5.43 g,69%); ¹H NMR (300 MHz, d₆-DMSO) δ 7.44 (d, J=7.5 Hz, 1H), 7.21-7.37 (m,4H), 6.93 (brs, 1H), 4.32 (s, 1H), 3.59 (s, 2H). LCMS-B: rt 4.734 min;m/z 160 [M+H] ⁺.

(d) 2-(2-((2-Chloro-5-methylpyrimidin-4-yl)ethynyl)phenyl)acetamide (I9)

A mixture of 2-(2-ethynylphenyl)acetamide (I8) (5.40 g, 33.9 mmol),2,4-dichloro-5-methylpyrimidine (6.63 g, 40.7 mmol) and CuI (0.129 g,0.678 mmol) in 1,4-dioxane (180 mL) and Et₃N (14.2 mL, 101 mmol) wasplaced under nitrogen. PdCl₂(PPh3)₂ (0.238 g, 0.339 mmol) was added andthe resulting mixture was stirred at 70° C. for 20 minutes, thenadsorbed onto silica gel and purified by column chromatography(CombiFlash Rf, 120 g SiO₂ Cartridge, 0-5% MeOH in DCM) to give thetitle compound I9 as a yellow solid (5.01 g, 51%); ¹H NMR (300 MHz,d₆-DMSO) δ 8.75 (s, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.35-7.52 (m, 4H), 6.97(brs, 1H), 3.71 (s, 2H), 2.42 (s, 3H). LCMS-B: rt 5.689 min; m/z 286[M+H] ⁺.

(e) 2-(2-(2-(2-Chloro-5-methylpyrimidin-4-ylethyl)phenyl)acetamide (K6)

A suspension of2-(2-((2-chloro-5-methylpyrimidin-4-yl)ethynyl)phenyl)acetamide (I9)(5.01 g, 17.5 mmol) in DMF (231 mL) and MeOH (80 mL) containing platinumoxide (0.995 g, 4.38 mmol) was stirred under a hydrogen atmosphere for40 hours. The resulting mixture was filtered through a pad of Celite andthe filtrate concentrated in vacuo. The resulting residue was dilutedwith ice water (400 mL) to give a precipitate, which was filtered anddried to give the title compound K6 (4.23 g, 83%); ¹H NMR (300 MHz,d₆-DMSO) δ 8.47 (s, 1H), 7.44 (brs, 1H), 7.21-7.24 (m, 1H), 7.12-7.15(m, 3H), 6.92 (brs, 1H), 3.47 (s, 2H), 2.99 (s, 4H), 2.15 (s, 3H).LCMS-B: rt 5.528 min; m/z 290 [M+H]⁺.

Key intermediate 7: Methyl2-(2-((2-chloro-5-methylpyrimidin-4-yl)ethynyl)phenyl)acetate (K7)

PPh₃ (31 mg, 0.12 mmol), PdCl₂(PPh₃)₂ (84 mg, 0.12 mmol), Et₃N (0.67 mL,4.8 mmol) and methyl 2-(2-ethynylphenyl)acetate (K1) (0.25 g, 1.4 mmol)were added to a solution of 2,4-dichloro-5-methylpyrimidine (0.20 g, 1.2mmol) in anhydrous DMF (5.0 mL). The solution was degassed with nitrogenfor 10 minutes before the addition of CuI (23 mg, 0.12 mmol). Theresulting mixture was heated under microwave irradiation at 120° C. for15 minutes then diluted with EtOAc (30 mL) and filtered through Celite.The filtrate was evaporated under reduced pressure and the resultingresidue adsorbed onto silica gel and purified by column chromatography(Biotage Isolera, 40 g SiO₂ cartridge, 0-35% EtOAc in petroleum benzine40-60° C.) to give the title compound K7 as a yellow solid (0.28 g,78%); ¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1H), 7.66 (d, J=7.7 Hz, 1H),7.46-7.40 (m, 1H), 7.39-7.31 (m, 2H), 3.93 (s, 2H), 3.71 (s, 3H), 2.45(s, 3H). LCMS-A: rt 5.993 min; m/z 301 [M+H]⁺.

Example 1 Synthesis of2-(2-(2-(2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(1)

(a) Methyl 2-(2-((2-(methylthio)pyrimidin-4-yl)ethynyl)phenyl)acetate(A1)

A suspension of 4-chloro-2-methylthiopyrimidine (200 μL, 1.72 mmol),PdCl₂(PPh₃)₂ (121 mg, 0.172 mmol), CuI (33.0 mg, 0.172 mmol), PPh₃ (45.0mg, 0.172 mmol), methyl 2-(2-ethynyl phenyl)acetate (K1) (359 mg, 1.08mmol) and Et₃N (0.938 mL) in THF (6 mL) was heated at 100° C. undermicrowave irradiation for 10 minutes. The volatiles were removed invacuo and the resultant residue adsorbed onto silica gel and purified bycolumn chromatography (Biotage Isolera, SiO₂ cartridge, 0-40% EtOAc inpetroleum benzine 40-60° C., then Biotage Isolera, SiO₂ cartridge, 0-40%EtOAc in DCM) to give the title compound A1 as a yellow oil (323 mg,63%); ¹H NMR (400 MHz, CDCl₃) δ 8.50 (d, J=5.0 Hz, 1H), 7.63 (dd, J=7.6,1.1 Hz, 1H), 7.44-7.29 (m, 3H), 7.12 (d, J=5.0 Hz, 1H), 3.92 (s, 2H),3.71 (s, 3H), 2.59 (s, 3H).

(b) Methyl 2-(2-(2-(2-(methylthio)pyrimidin-4-yl)ethyl)phenyl)acetate(A2)

A suspension of methyl2-(2-((2-(methylthio)pyrimidin-4-yl)ethynyl)phenyl)acetate (A1) (323 mg,1.08 mmol) and 10% Pd/C (300 mg) in DMF (15 mL) was stirred under ahydrogen atmosphere at room temperature for 20 hours. The resultingmixture was filtered through Celite, washing with EtOAc (100 mL). Thefiltrate was evaporated in vacuo to yield a brown oil which wasdissolved in DMF (10 mL). A slurry of 10% Pd/C (330 mg) in DMF (5 ml)was added and the resulting suspension was stirred under a hydrogenatmosphere at room temperature for a further 20 hours. The resultingmixture was filtered through Celite, washing with EtOAc (100 mL) thenthe filtrate was evaporated in vacuo. The resulting residue was adsorbedonto silica gel and purified by column chromatography (Biotage Isolera,12 g SiO₂ cartridge, 0-20% EtOAc in petroleum benzine 40-60° C.) toyield the title compound A2 as a clear oil (170 mg, 52%); ¹H NMR (400MHz, CDCl₃) δ 8.36 (d, J=5.0 Hz, 1H), 7.25-7.14 (m, 4H), 6.75 (d, J=5.1Hz, 1H), 3.69 (m, 5H), 3.11-3.04 (m, 2H), 2.99-2.91 (m, 2H), 2.57 (s,3H). LC-MS-A: rt 6.060 min; m/z 303.1 [M+H]⁺.

(c) Methyl2-(2-(2-(2-(methylsulfonyl)pyrimidin-4-yl)ethyl)phenyl)acetate (A3)

m-CPBA (70%; 174 mg, 1.01 mmol) was added to a solution of methyl2-(2-(2-(2-(methylthio)pyrimidin-4-yl)ethyl)phenyl)acetate (A2) (170 mg,0.458 mmol) in DCM (50 mL) at 0° C. The resulting mixture was stirred at0° C. for 1 hour, then warmed to room temperature and stirred for afurther 18 hours. The temperature was reduced to 0° C. and additionalm-CPBA (70%; 174 mg, 1.01 mmol) was added. After warming to roomtemperature, stirring was continued for a further 3 hours then 10%aqueous NaHCO3 (50 mL) was added. The layers were separated and theorganics were dried (MgSO4), evaporated under reduced pressure andadsorbed onto silica gel and purified by column chromatography (BiotageIsolera, SiO₂ cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) togive the title compound A3 as a clear oil (150 mg, 80%); ¹H NMR (400MHz, CDCl₃) δ 8.73 (d, J=5.1 Hz, 1H), 7.31 (d, J=5.1 Hz, 1H), 7.24-7.21(m, 1H), 7.21-7.18 (m, 2H), 7.14-7.09 (m, 1H), 3.70 (s, 3H), 3.68 (s,2H), 3.35 (s, 3H), 3.23-3.17 (m, 2H), 3.17-3.11 (m, 2H).

(d) Benzyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate(A4)

A solution of methyl2-(2-(2-(2-(methylsulfonyl)pyrimidin-4-yl)ethyl)phenyl)acetate (A3) (150mg, 449 μmol) and benzyl 4-(4-aminophenyl)piperazine-1-carboxylate (K2)(168 mg, 538 μmol) in TFE (5 mL) containing TFA (180 μL) was heated at100° C. under microwave irradiation for 60 minutes. Additional TFA (200μL) was added and the resulting solution heated at 120° C. undermicrowave irradiation for a further 40 minutes. Additional TFA (200 μL)was again added and the mixture was heated at 150° C. under microwaveirradiation for a further 20 minutes. The resulting mixture was adsorbedonto silica gel and purified by column chromatography (Biotage Isolera,SiO₂ cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give thetitle compound A4 as a brown oil (76 mg, 30%). LCMS-A: rt 6.212 min; m/z566.2 [M+H]⁺.

(e)2-(2-(2-(2-((4-(4-(Benzyloxy)carbonyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)aceticacid (A5)

LiOH.H₂O (40 mg, 0.93 mmol) was added to a solution of benzyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate(A4) (76 mg, 0.13 mmol) in THF (7 mL), water (1.5 mL) and MeOH (1 mL)and the resulting mixture was stirred at room temperature for 16 hours.The volatiles were removed in vacuo and the resultant residue wasdiluted with EtOAc (50 mL) and saturated aqueous NaHCO₃ (50 mL). Thelayers were separated and the aqueous layer was extracted with EtOAc(2×50 mL). The organic layers were combined, washed with brine (50 mL),dried over MgSO₄, filtered and concentrated under reduced pressure togive the title compound A5 as yellow oil; LCMS-A: rt 5.803 min; m/z552.1 [M+H]⁺.

(f) Benzyl4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate(A6)

HOBt (24 mg, 0.17 mmol), EDCl.HCl (33 mg, 0.17 mmol) and DI PEA (0.12mL, 0.67 mmol) were added to a stirred solution of2-(2-(2-(2-((4-(4-((benzyloxy)carbonyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)aceticacid (A5) (74 mg, 0.13 mmol) in dry THF (5 mL) and dry DMF (2 mL) underan atmosphere of nitrogen. After 10 minutes ammonium carbonate (65 mg,0.67 mmol) was added and stirring was continued at room temperature for18 hours. The volatiles were removed in vacuo and the residue wasdiluted with EtOAc (65 mL) and saturated NaHCO₃ (65 mL). The aqueouslayer was extracted with EtOAc (2×50 mL) then the combined organiclayers were washed with brine (50 mL) and dried over Na₂SO₄. Afterfiltration the solvent was removed in vacuo to afford a pale yellowsolid which was purified by silica gel column chromatography (BiotageIsolera, SiO₂ cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) togive the title compound A6 as brown oil (70 mg, 95%); ¹H-NMR (400 MHz,CDCl₃) δ 8.20 (s, 1H), 7.64 (s, 1H), 7.48 (d, J=8.9 Hz, 2H), 7.37 (d,J=4.3 Hz, 4H), 7.32 (m, 1H), 7.25-7.17 (m, 4H), 6.91 (d, J=9.0 Hz, 2H),6.51 (d, J=4.9 Hz, 1H), 5.77 (s, 1H), 5.51 (s, 1H), 5.16 (s, 2H),3.69-3.64 (m, 4H), 3.64 (s, 2H), 3.11-3.06 (m, 4H), 3.05 (dd, J=9.6, 6.5Hz, 2H), 2.91-2.84 (m, peak obscured), 2.07 (t, J=7.0 Hz 1H). LCMS-A: rt5.646 min; m/z 551.2 [M+H]⁺.

(g)2-(2-(2-(2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(1)

To a solution of benzyl4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate(A6) (73 mg, 0.13 mmol) in DMF (5 mL) under nitrogen, was added a slurryof 10% Pd/C (20 mg) in DMF. The resulting mixture was stirred under anatmosphere of hydrogen at room temperature for 19 hours then filteredthrough a 2.0 PFTE filter. The filtrate was evaporated in vacuo and theresidue was loaded onto a SCX (5 g) column using MeOH. The column waswashed with 2 column volumes of MeOH followed by 3 column volumes of 1%MeNH₂ in MeOH. The 1% MeNH₂ in MeOH filtrate was evaporated in vacuo togive a pale brown oil which was taken up in DCM (0.5 mL) and cyclohexane(1 mL) and sonicated. The resulting precipitate was filtered and thefilter cake dried in vacuo to give the title compound 1 as a white solid(1.4 mg, 90% purity). ¹H-NMR: (400 MHz, d4-MeOH) δ 8.22-8.16 (m, 1H),7.57-7.48 (m, 2H), 7.20 (m, 4H), 7.01-6.93 (m, 2H), 6.60 (dd, J=5.0, 2.8Hz, 1H), 3.63 (d, J=2.3 Hz, 2H), 3.18-3.12 (m, 4H), 3.09 (dd, J=9.2, 6.4Hz, 5H), 2.93-2.83 (m, 3H). LC-MS Method A: rt 4.305 min; m/z 417.2[M+H]⁺.

Example 2 Synthesis of2-(2-(2-(5-methyl-2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(2)

(a) tert-Butyl4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-methylpyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate(A7)

A mixture of tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (K3)(0.845 g, 3.06 mmol), methyl2-(2-((2-chloro-5-methylpyrimidin-4-ylethynyl)phenyl)acetate (K7) (0.460g, 1.53 mmol), Pd₂(dba)₃ (0.070 g, 0.076 mmol), Xantphos (0.089 g, 0.15mmol), and Na₂CO₃ (0.648 g, 6.12 mmol) in DME (16 mL) was degassed withnitrogen before heating under microwave irradiation for 30 minutes at110° C., then a further 60 minutes at 110° C. An additional 0.1equivalent of Pd₂(dba)₃ and 0.1 equivalent of Xantphos were added beforethe solution was degassed with nitrogen for 5 minutes and heated undermicrowave irradiation for 60 minutes at 110° C. The resulting mixturewas filtered and the filtrate evaporated in vacuo to give a dark brownresidue which was adsorbed onto silica gel and purified by columnchromatography (Biotage Isolera, 40 g SiO₂ cartridge, 0-100% MeOH inEtOAc), to yield the title compound A7 as brown oil (66 mg, 8%); ¹H NMR(400 MHz, CDCl₃) δ 8.27 (s, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.53-7.46 (m,2H), 7.44-7.28 (m, 4H), 6.94 (dd, J=7.2, 5.1 Hz, 2H), 3.96 (s, 2H), 3.70(s, 3H), 3.58 (dd, J=11.4, 6.2 Hz, 4H), 3.11-3.04 (m, 4H), 2.33 (s, 3H),1.49 (s, 9H). LC-MS-A: rt 6.409 min; m/z 542 [M+H]⁺.

(b) tert-Butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate(A8)

To a solution of tert-butyl4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-methylpyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (A7) (60 mg,0.11 mmol) in anhydrous DMF (10 mL) was added a slurry of 10% Pd/C (30mg) in DMF (2 mL). The resulting mixture was stirred at room temperatureunder an atmosphere of hydrogen for 72 hours then diluted with EtOAc (30mL) and filtered through a plug of Celite, washing with EtOAc (50 mL).The filtrate was evaporated to dryness to give the title compound A8 asa brown oily residue (44 mg, 73%); ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s,1H), 7.52 (dt, J=8.0, 2.5 Hz, 2H), 7.25-7.17 (m, 4H), 6.92 (dd, J=7.2,5.1 Hz, 2H), 6.88 (s, 1H), 3.72 (s, 2H), 3.68 (d, J=3.0 Hz, 3H),3.61-3.56 (m, 4H), 3.07 (dd, J=9.3, 5.1 Hz, 6H), 2.06 (s, 3H), 1.48 (s,9H). LC-MS-A: rt 6.260 min; m/z 546.2 [M+H]⁺.

(c)2-(2-(2-(2-((4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetic acid (A9)

LiOH.H₂O (24 mg, 0.56 mmol) was added to a solution of tert-butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate(A8) (44 mg, 0.081 mmol) in THF (7 mL), water (1.5 mL) and MeOH (1 mL)and the resulting mixture was stirred at room temperature for 24 hours.The volatiles were removed in vacuo and the resulting residue wasdiluted with EtOAc (50 mL) and saturated aqueous NaHCO₃ (50 mL). Thelayers were separated and the aqueous layer was extracted with EtOAc(2×50 mL). The organic layers were combined, washed with brine (50 mL),dried over MgSO₄, filtered and concentrated under reduced pressure togive the title compound A9 as brown oily residue (36 mg, 84%); LCMS-A:rt 5.737 min; m/z 532.2 [M+H]⁺.

(d) tert-Butyl4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate(A10)

HOBt (15 mg, 0.11 mmol), EDCl.HCl (21 mg, 0.11 mmol) and DIPEA (72 μL,0.41 mmol) were added to a solution of2-(2-(2-(2-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)ethyl)phenyl)aceticacid (A9) (44 mg, 0.083 mmol) in dry DMF (10 mL) under an atmosphere ofnitrogen. After 10 minutes ammonium carbonate (40 mg, 0.41 mmol) wasadded and the resulting mixture was stirred at room temperature for 18hours. A solution of HOBt (15 mg, 0.11 mmol), EDCl.HCl (21 mg, 0.11mmol) and DIPEA in DMF (3 mL) was then added and after 10 minutesammonium carbonate (40 mg, 0.41 mmol) was added in one portion. Theresulting mixture was stirred at 26° C. for a further 24 hours beforethe volatiles were removed in vacuo and the residue partitioned betweenEtOAc (65 mL) and saturated NaHCO₃ (65 mL). The aqueous layer wasextracted with EtOAc (2×50 mL) then the combined organics were washedwith brine (50 mL) and dried over Na₂SO₄. After filtration the solventwas removed in vacuo to afford a pale yellow solid which was adsorbedonto silica gel and purified by column chromatography (Biotage Isolera,SiO₂ cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. then 0-100%MeOH in EtOAc). After removing the solvent in vacuo the resultingresidue was taken up in EtOAc, filtered through cotton wool and thefiltrate evaporated to dryness to give the title compound A10 as a lightbrown solid (28 mg, 64%); ¹H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H),7.47-7.41 (m, 2H), 7.25-7.17 (m, 4H), 7.13 (s, 1H), 6.93-6.88 (m, 2H),5.59 (s, 1H), 5.53 (s, 1H), 3.65 (s, 2H), 3.61-3.55 (m, 4H), 3.10-3.01(m, 6H), 2.92-2.88 (m, 2H), 2.08 (s, 3H), 1.48 (s, 9H). LCMS-A: rt 5.525min; m/z 531.2 [M+H]⁺

(e) 2-(2-(2-(5-Methyl-2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide (2)

To a solution of tert-butyl4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate(A10) (28 mg, 0.053 mmol) in DCM (8 mL) was added TFA (2 mL) and theresulting solution was stirred at 25° C. for 24 hours. The volatileswere removed in vacuo and the residue was partitioned between EtOAc (10mL) and 2 M NaOH (20 mL). The aqueous layer was extracted with EtOAc(2×10 mL) then the combined organic layers washed with brine (10 mL) anddried (MgSO₄). The solvent was removed in vacuo to give a brown solidwhich was taken up in MeOH and purified by SCX cartridge (5 g, MeOHfollowed by 0.5 M NH₃ in MeOH). The volatiles from the ammoniacalfiltrate were removed in vacuo and the resulting solid residue suspendedin cyclohexane and sonicated. The resulting suspension was filtered andthe filter cake dried to give the title compound 2 as a light brownsolid (8 mg, 35%); ¹H NMR (400 MHz, d₆-DMSO) δ 9.08 (s, 1H), 8.11 (s,1H), 7.60 (dd, J=9.2, 2.2 Hz, 2H), 7.41 (s, 1H), 7.26-7.20 (m, 1H),7.19-7.13 (m, 3H), 6.92 (s, 1H), 6.85 (d, J=9.1 Hz, 2H), 4.02 (s, 1H),3.50 (s, 2H), 3.03 (dd, J=10.1, 5.7 Hz, 2H), 2.97 (m, 2H), 2.85 (m, 4H),2.69-2.64 (m, 2H), 2.36-2.30 (m, 2H), 2.05 (s, 3H). LCMS-A: rt 4.364min; m/z 431.1 [M+H]⁺.

Example 3 Synthesis of2-(2-(2-(2-((4-(aminomethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (3)

(a) tert-Butyl 4-aminobenzylcarbamate (A11)

Boc anhydride (4.46 g, 20.5 mmol) was added to a stirred solution of4-aminobenzylamine (2.50 g, 20.5 mmol) and Et₃N (5.70 mL, 40.9 mmol) inDCM (100 mL) at room temperature. The resulting mixture was stirredovernight before the volatiles were removed in vacuo. The residue wasadsorbed onto silica gel and purified by column chromatography (BiotageIsolera, SiO₂ cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) toyield the title compound A11 as a yellow solid (4.28 g, 94%); ¹H NMR(400 MHz, CDCl₃) δ 7.09 (d, J=8.2 Hz, 2H), 6.69-6.64 (m, 2H), 4.73 (s,1H), 4.21 (d, J=5.4 Hz, 2H), 3.66 (s, 2H), 1.48 (s, 9H). LCMS-A: rt4.363 min.

(b) tert-Butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzylcarbamate(A12)

A 1.0 M ZnCl₂ solution in Et₂O (5.40 mL, 5.40 mmol) was added cautiouslyto a stirred suspension of 2,4-dichloro-5-(trifluoromethyl)pyrimidine(1.03 g, 4.72 mmol) in 1:1 t-BuOH:DCE (200 mL) at room temperature.After stirring for 20 minutes, tert-butyl 4-aminobenzylcarbamate (A11)(1.00 g, 4.50 mmol) was added followed by Et₃N (752 μL, 5.40 mmol) andthe resulting mixture stirred at room temperature overnight. Thevolatiles were removed in vacuo and the resulting tan solid wassuspended in water (500 mL). The suspension was sonicated for 10minutes, filtered and the filter cake was washed with water (2×100 mL)then dried under high vacuum to give the title compound A12 as a tansolid (1.77 g, 97%); ¹H NMR (400 MHz, d₆-DMSO) δ 10.63 (s, 1H), 8.79 (s,1H), 7.61 (d, J=8.1 Hz, 2H), 7.36 (t, J=7.6 Hz, 1H), 7.22 (d, J=8.4 Hz,2H), 4.10 (d, J=6.0 Hz, 2H), 1.40 (s, 9H). LCMS-A: rt 6.356 min; m/z 401[M−1]⁻.

(c) Methyl2-(2-((2-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetate (A13)

A suspension of tert-butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzylcarbamate(A12) (500 mg, 1.24 mmol), CuI (12 mg, 0.06 mmol), PPh₃ (16 mg, 0.06mmol), and Et₃N (346 μL, 2.28 mmol) in DMF (3 mL) was sonicated for 5minutes before the addition of PdCl₂(PPh₃)₂ (44 mg, 0.06 mmol) andmethyl 2-(2-ethynylphenyl)acetate (K1) (324 mg, 1.86 mmol). Theresulting mixture was heated under microwave irradiation at 120° C. for20 minutes then adsorbed onto silica gel and purified by columnchromatography (Biotage Isolera, SiO₂ cartridge, 0-100% EtOAc inpetroleum benzine 40-60° C.) to yield a yellow solid. The solid wassuspended in toluene and the resulting suspension sonicated for 10minutes. The resulting suspension was filtered and the filter cake driedto give the title compound A13 as a yellow solid (412 mg, 61%); ¹H NMR(400 MHz, d₆-DMSO) δ 10.44 (s, 1H), 8.82 (s, 1H), 7.68 (d, J=8.4 Hz,2H), 7.63 (d, J=7.6 Hz, 1H), 7.58-7.52 (m, 1H), 7.50-7.40 (m, 2H), 7.36(t, J=6.0 Hz, 1H), 7.22 (d, J=8.5 Hz, 2H), 4.10 (d, J=6.0 Hz, 2H), 3.96(s, 2H), 3.62 (s, 3H), 1.40 (s, 9H). LCMS-A: rt 6.497 min; m/z 539[M−1]⁻.

(d) Methyl2-(2-(2-(2-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (A14)

A suspension of 10% Pd/C (200 mg) and methyl2-(2-((2-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetate (A13) (412 mg,0.762 mmol) in DMF (5 mL) and Et₃N (1 mL) was stirred under a hydrogenatmosphere at room temperature for 16 h. The resulting mixture wasfiltered through Celite, washing with EtOAc (200 mL) then the combinedfiltrates were evaporated in vacuo to give the title compound A14 as awhite solid (306 mg, 74%); ¹H NMR (400 MHz, d₆-DMSO) δ 10.19 (s, 1H),8.68 (s, 1H), 7.68 (d, J=8.5 Hz, 2H), 7.34 (t, J=6.0 Hz, 1H), 7.27-7.16(m, 6H), 4.09 (d, J=6.0 Hz, 2H), 3.76 (s, 2H), 3.59 (s, 3H), 3.11-2.95(m, 4H), 1.40 (s, 9H). LCMS-A: rt 6.637 min; m/z 545 [M+H]⁺.

(e) 2-(2-(2-(2-((4-(((tert-Butoxycarbonyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid (A15)

LiOH.H₂O (94 mg, 2.2 mmol) was added to a solution of methyl2-(2-(2-(2-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (A14) (306 mg, 0.562 mmol) in MeOH (1 mL),water (1 mL) and THF (10 mL) and the resulting mixture was stirred atroom temperature overnight. The volatiles were removed in vacuo and theresultant oil partitioned between EtOAc (150 mL) and 2 M aqueous NaOH(100 mL). The organic layer was separated, washed with water (2×100 mL),brine (50 mL) and dried over MgSO₄. The volatiles were removed in vacuoto yield the title compound A15 as a yellow oil (0.25 g, 83%); LCMS-A:rt 6.267 min; m/z 531 [M+H]⁺.

(f) tert-Butyl4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzylcarbamate(A16)

HOBt (76 mg, 0.56 mmol) and EDCl.HCl (108 mg, 0.561 mmol) were added toa solution of2-(2-(2-(2-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid (A15) (251mg, 0.468 mmol) and DIPEA (326 μL, 1.87 mmol) in DMF (2 mL) and THF (10mL). The resulting mixture was stirred at room temperature overnightthen the volatiles were removed in vacuo and the residue partitionedbetween EtOAc (150 mL) and saturated aqueous NaHCO₃ (100 mL). The layerswere separated and the organic layer was washed with water (100 mL),brine (50 mL) and dried over MgSO₄. The volatiles were removed in vacuoand the residue adsorbed onto silica gel and purified by silica gelcolumn chromatography (Biotage Isolera, SiO₂ cartridge, 0-100% EtOAc inpetroleum benzine 40-60° C.) to give the title compound A16 as a tansolid (0.22 g, 89%); ¹H NMR (400 MHz, d₆-DMSO) δ 10.18 (s, 1H), 8.67 (s,1H), 7.68 (d, J=8.5 Hz, 2H), 7.43 (s, 1H), 7.33 (t, J=6.0 Hz, 1H),7.27-7.10 (m, 6H), 6.91 (s, 1H), 3.50 (s, 2H), 3.18 (d, J=5.3 Hz, 2H),3.14-2.99 (m, 4H), 1.40 (s, 9H). LCMS-A: rt 6.086 min; m/z 530 [M+H]⁺.

(g)2-(2-(2-(2-((4-(Aminomethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(3)

TFA (954 μL, 12.5 mmol) was added to a solution of tert-butyl4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzylcarbamate(A16) (220 mg, 0.415 mmol) in DCM (10 mL) and the resulting mixturestirred for 20 hours at room temperature. The volatiles were removed invacuo and the resulting residue partitioned between EtOAc (100 mL) and 2M aqueous NaOH (100 mL). The layers were separated and the organic layerwashed with water (100 mL), brine (50 mL), dried (MgSO₄) then evaporatedin vacuo to yield a white solid. The solid was taken up in DCM (10 mL)and sonicated for 2 minutes then petroleum benzine 40-60° C. (100 mL)was added and sonication continued for a further 10 minutes. Theresulting suspension was filtered and the filter cake dried to give thetitle compound 3 as a white solid (135 mg, 76%); ¹H NMR (400 MHz,d₄-MeOH) δ 8.57 (s, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H),7.31-7.17 (m, 4H), 3.81 (s, 2H), 3.69 (s, 2H), 3.22-3.06 (m, 4H).LCMS-A: rt 4.722 min; m/z 428 [M−1]⁻.

Example 4 Synthesis of2-(2-(2-(5-methyl-2-((6-(piperidin-4-yl)pyridin-3-yl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide (4)

(a) tert-Butyl4-(5-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-methylpyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate(A17)

To a solution of methyl2-(2-((2-chloro-5-methylpyrimidin-4-yl)ethynyl)phenyl)acetate (K7) (100mg, 0.333 mmol) in 1,4-dioxane (8 mL) was added tert-butyl4-(5-aminopyridin-2-yl)piperidine-1-carboxylate (K4) (92.2 mg, 0.333mmol), Cs₂CO₃ (433 mg, 1.33 mmol), Pd₂(dba)₃ (30 mg, 0.033 mmol) andXantphos (58 mg, 0.10 mmol). The resulting mixture was degassed withnitrogen for 5 minutes before heating under microwave irradiation for 30minutes at 120° C. The resulting mixture was diluted with EtOAc (100 mL)then washed with water (2×25 mL), brine (25 mL), dried (Na₂SO₄) andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (Biotage Isolera, 40 g SiO₂ cartridge, 0-100%EtOAc in hexanes) to give the title compound A17 as a yellow foam (112mg, 62%); ¹H NMR (400 MHz, CDCl₃) δ 8.62 (d, J=2.4 Hz, 1H), 8.32 (d,J=0.6 Hz, 1H), 8.16 (dd, J=8.5, 2.7 Hz, 1H), 7.66 (dd, J=7.6, 0.9 Hz,1H), 7.43-7.30 (m, 3H), 7.14 (d, J=8.5 Hz, 1H), 7.10 (s, 1H), 4.25 (br.s, 2H), 3.95 (s, 2H), 3.70 (s, 3H), 2.86-2.78 (m, 3H), 2.35 (d, J=0.4Hz, 3H), 1.91 (d, J=13.3 Hz, 2H), 1.75-1.63 (m, 2H), 1.47 (s, 9H).LCMS-A: rt 5.462 min; m/z 542 [M+H]⁺.

(b) tert-Butyl4-(5-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate(A18)

A suspension of 10% Pd/C (53% water; 30 mg) and tert-butyl4-(5-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-methylpyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate(A17) (125 mg, 0.231 mmol) in DMF (5 mL) and Et₃N (1 mL) was stirredunder a hydrogen atmosphere at room temperature for 44 hours. Theresulting mixture was filtered through Celite, washing with EtOAc (200mL). The combined filtrates were evaporated in vacuo and the resultingoil purified by silica gel chromatography (Biotage Isolera, 12 g SiO₂cartridge, 0-100% EtOAc in hexanes) to give the title compound A18 as ayellow foam (115 mg, 91%); ¹H NMR (400 MHz, CDCl₃) δ 8.62 (d, J=2.5 Hz,1H), 8.16 (dd, J=8.5, 2.7 Hz, 1H), 8.11 (d, J=0.5 Hz, 1H), 7.25-7.16 (m,5H), 7.11 (d, J=8.5 Hz, 1H), 4.25 (br. s, 2H), 3.71 (s, 2H), 3.67 (s,3H), 3.09 (dd, J=9.6, 6.1 Hz, 2H), 2.93 (dd, J=9.4, 6.0 Hz, 2H),2.88-2.76 (m, 3H), 2.08 (s, 3H), 1.91 (d, J=11.8 Hz, 2H), 1.75-1.61 (m,2H), 1.47 (s, 9H). LCMS-A: rt 5.401 min; m/z 546 [M+H]⁺.

(c)2-(2-(2-(2-((6-(1-(tert-Butoxycarbonyl)piperidin-4-yl)pyridin-3-yl)amino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetic acid (A19)

LiOH.H₂O (442 mg, 10.5 mmol) was added to a stirred solution oftert-butyl 4-(5-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate(A18) (115 mg, 0.211 mmol) in water (4 mL) and THF (40 mL) and theresulting mixture heated at 40° C. for 18 hours. On cooling thevolatiles were removed in vacuo and the residue taken up in EtOAc (100mL). The resulting solution was washed with water (100 mL), brine (50mL) and dried over MgSO₄. The volatiles were removed in vacuo to givethe title compound A19 as a clear oil (96 mg, 86%); LCMS-A: rt 5.137min; m/z 532 [M+H]⁺.

(d) tert-Butyl4-(5-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate(A20)

HOBt (71 mg, 0.52 mmol), EDCl.HCl (0.11 g, 0.59 mmol) and DIPEA (0.16mL, 0.90 mmol) were added to a stirred solution of2-(2-(2-(2-((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-3-yl)amino)-5-methylpyrimidin-4-ylethyl)phenyl)acetic acid(A19) (96 mg, 0.18 mmol) in dry DMF (5 mL) under an atmosphere ofnitrogen. After 10 minutes ammonium carbonate (174 mg, 1.81 mmol) wasadded in one portion and the resulting mixture was stirred for 18 hoursat room temperature. The volatiles were removed in vacuo and the residuewas partitioned between EtOAc (10 mL) and saturated aqueous NaHCO₃ (10mL). The aqueous layer was extracted with EtOAc (2×10 mL) then thecombined organic layers were washed with brine (10 mL) and dried overNa₂SO₄. The volatiles were removed in vacuo and the residue adsorbedonto silica gel and purified by chromatography (Biotage Isolera, 40 gSiO₂ cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. followed by0-25% MeOH in DCM) to give the title compound A20 as a clear oil (72 mg,75%). ¹H NMR (400 MHz, CDCl₃) δ 8.82 (d, J=2.4 Hz, 1H), 8.14-8.06 (m,1H), 7.93 (dd, J=8.5, 2.7 Hz, 1H), 7.37 (s, 1H), 7.26-7.22 (m, 4H), 7.10(d, J=8.5 Hz, 1H), 5.91 (s, 1H), 5.73 (s, 1H), 4.24 (s, 2H), 3.69 (s,2H), 3.09 (dd, J=9.7, 6.0 Hz, 2H), 2.97-2.90 (m, 2H), 2.86-2.72 (m, 3H),2.12 (s, 3H), 1.90 (d, J=12.8 Hz, 2H), 1.68 (m, 2H), 1.47 (s, 9H).LCMS-A: rt 5.018 min; m/z 531 [M+H]⁺.

(e)2-(2-(2-(5-Methyl-2-((6-(piperidin-4-yl)pyridin-3-yl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide (4)

TFA (0.5 mL) was added to a solution of tert-butyl4-(5-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate(A20) (70 mg, 0.13 mmol) in DCM (5 mL) and the resulting mixture stirredfor 18 hours at room temperature. The volatiles were removed in vacuoand the residue partitioned between 2 M aqueous NaOH (10 mL) and EtOAc(25 mL). The organic layer was separated then washed with water (25 mL),brine (25 mL), dried (Na₂SO₄) and concentrated under reduced pressure togive the title compound 4 as an off white solid (45 mg, 79%); ¹H NMR(400 MHz, d₄-MeOH) δ 8.79 (dd, J=2.6, 0.5 Hz, 1H), 8.15 (dd, J=8.6, 2.7Hz, 1H), 8.13 (d, J=0.6 Hz, 1H), 7.28-7.22 (m, 2H), 7.21-7.14 (m, 3H),3.64 (s, 2H), 3.20-3.10 (m, 4H), 3.02-2.95 (m, 2H), 2.88-2.68 (m, 3H),2.11 (s, 3H), 1.95-1.84 (m, 2H), 1.71 (qd, J=12.7, 4.0 Hz, 2H). LCMS-A:rt 4.241 min; m/z 431 [M+H]⁺.

Example 5 Synthesis of2-(2-(2-(5-methyl-2-((6-(1-methylpiperidin-4-yl)pyridin-3-yl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide (5)

Formaldehyde (37% wt. in H₂O; 0.017 mL, 0.22 mmol) was added to asolution of 2-(2-(2-(5-methyl-2-((6-(piperidin-4-yl)pyridin-3-yl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(4) (32 mg, 0.07 mmol) in MeOH (4 mL) under an atmosphere of nitrogen.The resulting solution was stirred for 15 minutes at room temperaturethen sodium triacetoxyborohydride (63 mg, 0.30 mmol) was added in oneportion. After stirring at room temperature for 18 hours a furtherportion of formaldehyde (37 wt. % in H₂O; 0.017 mL, 0.22 mmol) was addedand after 15 minutes sodium triacetoxyborohydride (63 mg, 0.30 mmol) wasadded in one portion. The resulting mixture was stirred at roomtemperature for 20 hours then the volatiles were removed in vacuo andthe residue partitioned between EtOAc (50 mL) and saturated aqueousNaHCO₃ (50 mL). The layers were separated and the aqueous layer wasextracted with EtOAc (2×25 mL). The combined organic layers were washedwith water (25 mL), brine (25 mL) and dried over Na₂SO₄. The volatileswere removed under reduced pressure to give the title compound 5 as anoff white solid (20 mg, 61%); ¹H NMR (400 MHz, d₄-MeOH) δ 8.79 (d, J=2.2Hz, 1H), 8.15 (dd, J=8.6, 2.7 Hz, 1H), 8.12 (d, J=0.6 Hz, 1H), 7.27-7.23(m, 2H), 7.20-7.15 (m, 3H), 3.64 (s, 2H), 3.16-3.06 (m, 4H), 2.98 (dd,J=9.2, 6.0 Hz, 2H), 2.72 (tt, J=12.0, 3.9 Hz, 1H), 2.40 (s, 3H), 2.32(td, J=12.0, 2.4 Hz, 2H), 2.11 (s, 3H), 1.97 (d, J=11.9 Hz, 2H),1.92-1.80 (m, 2H). LCMS-A: rt 4.237 min; m/z 445 [M+H]⁺.

Example 6 Synthesis of2-(2-(2-(2-((4-(piperazine-1-carbonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (6)

(a) tert-Butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate (A21)

To a solution of 4-aminobenzoic acid (0.411 g, 3.00 mmol) in DMF (5.0mL) at room temperature was added EDCl.HCl (0.862 g, 4.50 mmol), HOBt(0.608 g, 4.50 mmol), Et₃N (0.835 mL, 6.00 mmol) and N-Boc piperazine(0.671 g, 3.60 mmol). The resulting mixture was stirred at roomtemperature for 21 hours then 2 M aqueous NaOH was added to adjust thepH to >10. EtOAc was added then the layers separated and the organiclayer dried over MgSO₄. The volatiles were removed under reducedpressure and the residue was purified by silica gel chromatography(Biotage Isolera, 40 g SiO₂ cartridge, 50-90% EtOAc in petroleum benzine40-60° C.) to give the title compound A21 as a white solid (0.530 g,56%); LCMS-A: rt 5.079 min; m/z 250.1 [(M-t-Bu)+H]⁺, 206.1 [(M-Boc)+H]⁺.

(b) tert-Butyl4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)piperazine-1-carboxylate(A22)

Zinc(II) chloride (1.0 M in Et₂O; 2.00 mL, 2.00 mmol) was added to asolution of 2,4-dichloro-5 -(trifluoromethyl)pyrimidine (0.399 g, 1.84mmol) in 1:1 DCE/t-BuOH (15 mL) at 0° C. under a nitrogen atmosphere.The resulting mixture was stirred for 1 hour at 0° C. and thentert-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate (A21) (0.510 g,1.67 mmol) in 1:1 DCE/tBuOH (15 mL) was added. A solution of Et₃N (0.256mL, 1.84 mmol) in 1:1 DCE/t-BuOH (15 mL) was added dropwise at 0° C. andthe resulting mixture was vigorously stirred for a further 30 minutes at0° C. then at room temperature for 16 hours. The volatiles were removedin vacuo to afford a brown residue which was purified by silica gelcolumn chromatography (Biotage Isolera, 25 g SiO₂ cartridge, 0-100%EtOAc in petroleum benzine 40-60° C.) to yield a pale yellow solid. Thesolid was suspended in MeOH (15 mL) and water (15 mL) and the resultingsuspension filtered to give the title compound A22 as a white solid(0.561 g, 69%); ¹H NMR (400 MHz, CDCl₃) δ 8.61 (s, 1H), 7.68 (d, J=8.7Hz, 2H), 7.64 (s, 1H), 7.45 (d, J=8.6 Hz, 2H), 3.87-3.30 (m, 8H), 1.47(s, 9H). LCMS-A: rt 6.206 min; m/z 484.1 [M−H]⁻.

(c) tert-Butyl4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)piperazine-1-carboxylate(A23)

A solution of methyl 2-(2-ethynylphenyl)acetate (K1) (0.129 g, 0.741mmol) in DMF (3 mL) and Et₃N (344 μL, 2.47 mmol) was added to a mixtureof tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)piperazine-1-carboxylate(A22) (0.300 g, 0.617 mmol), PdCl₂ (PPh₃)₂ (0.065 g, 0.093 mmol), CuI(0.018 g, 0.093 mmol) and PPh₃ (0.016 g, 0.062 mmol) in DMF (3 mL). Theresulting mixture was heated under microwave irradiation at 120° C. for15 minutes, diluted with EtOAc and passed through a plug of Celite,washing with EtOAc (60 mL). The filtrates were combined and thevolatiles were removed in vacuo to give a residue that was purified bysilica gel column chromatography (Biotage Isolera, 25 g SiO₂ cartridge,0-80% EtOAc in petroleum benzine 40-60° C.) to give the title compoundA23 as a yellow oil (0.337 g, 88%); ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s,1H), 7.73 (d, J=8.6 Hz, 2H), 7.68 (dd, J=7.7, 1.0 Hz, 1H), 7.61 (s, 1H),7.48-7.41 (m, 3H), 7.40-7.31 (m, 2H), 3.96 (s, 2H), 3.71 (s, 3H),3.67-3.37 (m, 8H), 1.47 (s, 9H). LCMS-A: rt 6.393 min; m/z 624.1 [M+H]⁺.

(d) tert-Butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)piperazine-1-carboxylate(A24)

A suspension of 10% Pd/C (53% water; 0.660 g), tert-butyl4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)piperazine-1-carboxylate(A23) (0.337 g, 0.540 mmol) and Et₃N (1 mL) was stirred at roomtemperature for 16 hours under an atmosphere of hydrogen. The mixturewas filtered through a pad of Celite, washing with EtOAc (80 mL). Thefiltrates were evaporated in vacuo affording a yellow oil which waspurified by silica gel column chromatography (Biotage Isolera, 40 g SiO₂cartridge, 0-80% EtOAc in petroleum benzine 40-60° C.) to yield thetitle compound A24 as a pale yellow oil (0.245 g, 72%); ¹H NMR (400 MHz,CDCl₃) δ 8.54 (s, 1H), 8.19 (s, 1H), 7.72 (d, J=8.7 Hz, 2H), 7.41 (d,J=8.6 Hz, 2H), 7.25-7.13 (m, 4H), 3.73 (s, 2H), 3.65 (s, 3H), 3.84-3.30(m, 8H), 3.18-3.00 (m, 4H), 1.46 (s, 9H). LCMS-A: rt 6.500 min; m/z 628[M+H]⁺.

(e) tert-Butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)piperazine-1-carboxylate(A25)

LioH.H₂O (0.050 g, 1.2 mmol) was added to a solution of tert-butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)piperazine-1-carboxylate(A24) (0.25 g, 0.39 mmol) in THF (7 mL), water (1.5 mL) and MeOH (1 mL)and the resulting mixture was stirred at room temperature for 18 hours.The volatiles were removed in vacuo and the residue was partitionedbetween EtOAc (50 mL) and saturated aqueous NaHCO₃ (50 mL). The layerswere separated and the aqueous layer was extracted with EtOAc (2×50 mL).The combined organic layers were washed with brine (50 mL), dried overMgSO₄ and the volatiles removed in vacuo to give the title compound A25as a white solid (0.24 g, 99%). LCMS-A: rt 6.281 min; m/z 558[(M-t-Bu)+H]⁺, 514 ([M-Boc)+H]⁺.

(f) tert-Butyl4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)piperazine-1-carboxylate(A26)

HOBt (0.068 g, 0.50 mmol), EDCl.HCl (0.096 g, 0.50 mmol) and DIPEA (0.34mL, 1.9 mmol) were added to a stirred solution of tert-butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)piperazine-1-carboxylate(A25) (0.28 g, 0.39 mmol) in dry THF (6 mL) and dry DMF (1 mL) under anatmosphere of nitrogen. After 10 minutes ammonium carbonate (0.19 g, 1.9mmol) was added in one portion and the resulting solution was stirred atroom temperature for 17 hours. The volatiles were removed in vacuo andthe residue was partitioned between EtOAc (65 mL) and saturated aqueousNaHCO₃ (65 mL). The aqueous layer was extracted with EtOAc (2×50 mL)then the combined organic layers were washed with brine (50 mL) anddried over MgSO₄. The volatiles were removed in vacuo and the residuewas purified by silica gel column chromatography (Biotage Isolera, 25 gSiO₂ cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. then 0-20%MeOH in EtOAc) to give the title compound A26 as a white solid (0.18 g,77%); ¹H NMR (400 MHz, CDCl₃) δ 8.58 (s, 1H), 7.91 (s, 1H), 7.72 (d,J=8.4 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.31-7.21 (m, obscured), 5.43(br. s, 2H), 3.74 (s, 2H), 3.71-3.35 (m, 8H), 3.18-3.03 (m, 4H), 1.47(s, 9H). LCMS-A: rt 6.120 min; m/z 613.3 [M+H]⁺.

(g)2-(2-(2-(2-((4-(piperazine-1-carbonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (6)

To a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)piperazine-1-carboxylate(A26) (0.182 g, 0.297 mmol) in DCM (4 mL) was added TFA (1 mL) and theresulting mixture was stirred at room temperature for 16 hours. Thevolatiles were removed in vacuo and the residue partitioned betweenEtOAc (10 mL) and 2 M aqueous NaOH (10 mL). The aqueous layer wasextracted with EtOAc (2×10 mL) then the combined organic fractions werewashed with water (10 mL), brine (10 mL) and dried over MgSO₄. Thevolatiles were removed in vacuo to give a yellow solid, which wassuspended in cyclohexane and then filtered to give the title compound 6as a white solid (0.132 g, 87%); ¹H NMR (400 MHz, d₄-MeOH) δ 8.62 (s,1H), 7.83 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.8 Hz, 2H), 7.27 (d, J=6.3 Hz,1H), 7.23-7.15 (m, 3H), 3.68 (s, 2H), 3.82-3.46 (m, 4H), 3.23-3.15 (m,2H), 3.12 (dd, J=9.8, 5.4 Hz, 2H), 3.02-2.71 (m, 4H). LCMS-A: rt 4.676min; m/z 513.3 [M+H]⁺.

Example 7 Synthesis of2-(2-(2-(2-((3-fluoro-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (7)

tert-Butyl4-(2-fluoro-4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (A27)

To a mixture of 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronicacid pinacol ester (0.555 g, 1.80 mmol), 4-bromo-3-fluoronitrobenzene(0.294 g, 1.33 mmol) and PdCl₂(PPh₃)2 (0.051 g, 0.072 mmol) undernitrogen was added 1,4-dioxane (5.0 mL) and 3 M aqueous Na₂CO₃ (1.4 mL,4.2 mmol). The resulting solution was degassed with a stream of nitrogenfor 10 minutes then heated at reflux for 16 hours. The volatiles wereevaporated under reduced pressure and the residue purified using silicagel column chromatography (Biotage Isolera, SiO₂ cartridge, 0-25% EtOAcin petroleum benzine 40-60° C.) to give the title compound A27 (0.391 g,91%); ¹H NMR (400 MHz, CDCl₃) δ 8.01 (m, 1H), 7.93 (dd, J=10.6, 2.2 Hz,1H), 7.42 (dd, J=8.5, 7.6 Hz, 1H), 6.11 (s, 1H), 4.12 (m, 2H), 3.64 (t,J=5.6 Hz, 2H), 2.52 (brs, 2H), 1.50 (s, 9H).

(b) tert-Butyl 4-(4-amino-2-fluorophenyl)piperidine-1-carboxylate (A28)

To a solution of tert-butyl4-(2-fluoro-4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (A27)(0.391 g, 1.20 mmol) in EtOAc (10 mL) was added 10% Pd/C (0.118 g) inEtOAc (1 mL) and the resulting suspension was stirred at 30° C. under ahydrogen atmosphere for 16 hours. The resulting mixture was filteredthrough Celite and the filtrate concentrated under reduced pressure togive the title compound A28 (0.339 g, 96%); ¹H NMR (400 MHz, CDCl₃) δ6.94 (dd, J=8.3 Hz, 1H), 6.41 (dd, J=8.2, 2.4 Hz, 1H), 6.36 (dd, J=12.1,2.3 Hz, 1H), 4.21 (brs, 2H), 3.65 (s, 2H), 2.84 (m, 3H), 1.75 (bd,J=13.3 Hz, 2H), 1.47 (s, 9H).

(c) tert-Butyl4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate(A29)

Zinc(II) chloride (1.0 M in Et₂O; 1.08 mL, 1.08 mmol) was added to asolution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.216 g, 0.994mmol) in 1:1 DCE/t-BuOH (8 mL) at 0° C. under a nitrogen atmosphere. Theresulting mixture was stirred for 1 hour at 0° C. then tert-butyl4-(4-amino-2-fluorophenyl)piperidine-1-carboxylate (A28) (0.266 g, 0.904mmol) in 1:1 DCE/t-BuOH (8 mL) was added. A solution of Et₃N (0.139 mL,0.994 mmol) in 1:1 DCE/t-BuOH (5 mL) was then added dropwise at 0° C.and the resulting mixture was vigorously stirred for a further 30minutes at 0° C., then at room temperature for 18 hours. The volatilesremoved in vacuo to afford a brown residue which was purified by silicagel column chromatography (Biotage Isolera, 25 g SiO₂ Cartridge, 0-20%EtOAc in petroleum benzine 40-60° C.) to yield a pale yellow solid. Thesolid was suspended in MeOH (15 mL) and water (15 mL) and the resultingsuspension filtered to afford the title compound A29 as a white solid(0.363 g, 85%); ¹H NMR (400 MHz, CDCl₃) δ 8.59 (s, 1H), 7.59-7.47 (m,2H), 7.20-7.14 (m, 1H), 4.37-4.14 (m, 2H), 2.98 (tt, J=12.1, 3.4 Hz,1H), 2.83 (t, J=11.7 Hz, 2H), 1.80 (d, J=12.8 Hz, 2H), 1.71-1.55 (m,3H), 1.48 (s, 9H). LCMS-A: rt 6.902 min; m/z 473.1 [M−H]⁻.

(d) tert-Butyl4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate(A30)

A solution of methyl 2-(2-ethynylphenyl)acetate (K1) (0.15 g, 0.87 mmol)in DMF (3 mL) and Et₃N (0.40 mL, 2.9 mmol) were added to a mixture oftert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate(A29) (0.34 g, 0.72 mmol), PdCl₂(PPh₃)₂ (0.076 g, 0.11 mmol), CuI (0.021g, 0.072 mmol) and PPh₃ (0.019 g, 0.072 mmol) in DMF (3 mL). Theresulting mixture was heated under microwave irradiation at 120° C. for15 minutes then diluted with EtOAc and passed through a plug of Celite,washing with EtOAc (60 mL). The filtrates were combined and thevolatiles were removed in vacuo to give a brown residue. The residue waspurified by silica gel column chromatography (Biotage Isolera, 40 g SiO₂cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to give the titlecompound A30 as a yellow oil (0.40 g, 90%); ¹H NMR (400 MHz, CDCl₃) δ8.65 (s, 1H), 7.70-7.60 (m, 2H), 7.50 (s, 1H), 7.47-7.41 (m, 1H),7.40-7.31 (m, 2H), 7.22-7.12 (m, 2H), 4.36-4.18 (m, 2H), 3.96 (s, 2H),3.71 (s, 3H), 2.98 (tt, J=12.1, 3.4 Hz, 1H), 2.83 (t, J=12.0 Hz, 2H),1.81 (d, J=12.4 Hz, 2H), 1.70-1.55 (m, obscured), 1.49 (s, 9H). LCMS-A:rt 7.010 min; m/z 613.1 [M+H]⁺.

(e) tert-Butyl4-(2-fluoro-4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A31)

To a solution of tert-butyl4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate(A30) (0.399 g, 0.651 mmol) in DMF (6 mL) and Et₃N (1 mL) was added aslurry of 10% Pd/C (53% water; 0.500 g) in DMF (3 mL). The resultingmixture was stirred at room temperature for 21 hours under an atmosphereof hydrogen then filtered through a pad of Celite, washing with EtOAc(80 mL). The filtrates were concentrated in vacuo and the residuepurified by silica gel chromatography (Biotage Isolera, 25 g SiO₂cartridges, 0-40% EtOAc in petroleum benzine 40-60° C.) to yield thetitle compound A31 as a pale yellow solid (0.312 g, 78%); ¹H NMR (400MHz, CDCl₃) δ 8.56 (s, 1H), 7.66 (dd, J=12.7, 2.0 Hz, 1H), 7.45 (s, 1H),7.29-7.12 (m, obscured by solvent), 4.41-4.16 (m, 2H), 3.77 (s, 2H),3.68 (s, 3H), 3.18-3.06 (m, 4H), 2.97 (tt, J=11.9, 3.3 Hz, 1H), 2.83 (t,J=12.8 Hz, 2H), 1.81 (d, J=12.1 Hz, 2H), 1.71-1.52 (m, obscured), 1.49(s, 9H). LCMS-A: rt 7.221 min; m/z 617.1 [M+H]⁺.

(f) tert-Butyl4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate(A32) LiOH.H₂O (0.063 g, 1.5 mmol) was added to a solution of tert-butyl4-(2-fluoro-4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A31) (0.30 g, 0.49 mmol) in THF (10 mL), water (2 mL) and MeOH (1.5 mL)and the resulting mixture was stirred at room temperature for 18 hours.The volatiles were removed in vacuo and the residue was partitionedbetween EtOAc (50 mL) and saturated aqueous NaHCO₃ (50 mL). The layerswere separated and the aqueous layer was extracted with EtOAc (2×50 mL).The combined organic layers were washed with brine (50 mL), dried(MgSO₄) and the volatiles removed in vacuo to give a white solid. Thesolid was dissolved in dry THF (12 mL) and dry DMF (2 mL) under anatmosphere of nitrogen and HOBt (0.086 g, 0.64 mmol), EDCl.HCl (0.12 g,0.64 mmol) and DIPEA (0.43 mL, 2.4 mmol) were added. After 10 minutesammonium carbonate (0.24 g, 2.4 mmol) was added in one portion and theresulting mixture was stirred at room temperature for 18 hours. Thevolatiles were removed in vacuo and the residue was partitioned betweenEtOAc (65 mL) and saturated aqueous NaHCO₃ (65 mL). The aqueous layerwas extracted with EtOAc (2×50 mL) then the combined organic layers werewashed with brine (50 mL) and dried over MgSO₄. The volatiles wereremoved in vacuo to afford a pale yellow oil which was purified bysilica gel column chromatography (Biotage Isolera, SiO₂ cartridge, 0-80%EtOAc in petroleum benzine 40-60° C.) to give the title compound A32 asa white solid (0.209 g, 69%); ¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1H),8.44 (s, 1H), 7.61 (dd, J=12.8, 2.2 Hz, 1H), 7.30-7.18 (m, 5H), 7.09 (t,J=8.4 Hz, 1H), 6.31 (s, 1H), 5.69 (s, 1H), 4.39-4.16 (m, 2H), 3.72 (s,2H), 3.14-3.00 (m, 4H), 2.94 (tt, J=12.1, 3.3 Hz, 1H), 2.81 (t, J=11.4Hz, 2H), 1.78 (d, J=12.2 Hz, 2H), 1.69-1.53 (m, 2H), 1.49 (s, 9H).LCMS-A: rt 6.710 min; m/z 602.3 [M+H]⁺.

(g)2-(2-(2-(2-((3-Fluoro-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(7)

To a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate(A32) (0.209 g, 0.347 mmol) in DCM (4 mL) was added TFA (1.0 mL) and theresulting mixture was stirred at room temperature for 16 hours. Thevolatiles were removed in vacuo and the residue partitioned betweenEtOAc (10 mL) and 2 M aqueous NaOH (10 mL). The aqueous layer wasextracted with EtOAc (2×10 mL) then the combined organic layers washedwith water (10 mL), brine (10 mL) and dried over MgSO₄. The volatileswere removed in vacuo to give a yellow solid which was suspended inDCM/cyclohexane and the resulting suspension filtered to give the titlecompound 7 as a white solid (0.107 g, 61%); ¹H NMR (400 MHz, d₄-MeOH) δ8.59 (s, 1H), 7.66 (dd, J=13.2, 2.1 Hz, 1H), 7.39 (dd, J=8.5, 2.1 Hz,1H), 7.28-7.15 (m, 5H), 3.68 (s, 2H), 3.23-3.14 (m, 4H), 3.10 (dd,J=10.6, 5.4 Hz, 2H), 2.99 (tt, J=11.7, 3.8 Hz, 1H), 2.80 (td, J=12.4,2.9 Hz, 2H), 1.87-1.68 (m, 4H). LCMS-A: rt 4.851 min; m/z 502.2 [M+H]⁺.

Example 8 Synthesis of2-(2-(2-(2-((3-fluoro-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (8)

Formaldehyde (37 wt. % in H₂O; 0.041 mL, 0.50 mmol) was added to asuspension of 2-(2-(2-(2-((3-fluoro-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (7) (0.046 g, 0.092 mmol) in anhydrous MeOH(5 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride(0.19 g, 0.10 mmol) was then added in one portion and the resultingmixture stirred at room temperature for 3 hours. The volatiles wereremoved in vacuo and the residue was partitioned between EtOAc (10 mL)and saturated aqueous NaHCO₃ (10 mL). Solid NaHCO₃ was added until theformation of gas ceased, then the layers were separated and the aqueouslayer was extracted with EtOAc (2×100 mL). The organic layers werecombined, washed with water (10 mL), brine (10 mL) and dried overNa₂SO₄. The volatiles were removed under reduced pressure to yield thetitle compound 8 as a white solid (0.043 g, 92%); ¹H NMR (400 MHz,d₄-MeOH) δ 8.58 (s, 1H), 7.66 (dd, J=13.2, 2.0 Hz, 1H), 7.37 (dd, J=8.5,2.0 Hz, 1H), 7.28-7.14 (m, 5H), 3.68 (s, 2H), 3.20-3.12 (m, 2H),3.13-3.04 (m, 2H), 3.01 (d, J=12.0 Hz, 2H), 2.90-2.76 (m, 1H), 2.34 (s,3H), 2.24-2.12 (m, 2H), 1.90-1.77 (m, 4H). LCMS-A rt 4.888 min; m/z516.3 [M+H]⁺.

Example 9 Synthesis of2-(5-fluoro-2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (9)

(a) 2-(2-Bromo-5-fluorophenyl)acetamide (A33)

HOBt (0.435 g, 3.22 mmol), EDCl.HCl (0.617 g, 3.22 mmol) and DIPEA (1.87mL, 10.7 mmol) were added to a stirred solution of2-(2-bromo-5-phenyl)acetic acid (0.500 g, 2.15 mmol) in dry THF (6 mL)and dry DMF (1 mL) under an atmosphere of nitrogen. After 10 minutesammonium carbonate (1.03 g, 10.7 mmol) was added in one portion and theresulting mixture stirred at room temperature for 16 hours. Thevolatiles were removed in vacuo and the residue was partitioned betweenDCM (50 mL) and saturated aqueous NaHCO₃ (50 mL).The aqueous phase wasextracted with DCM (2×50 mL) then the combined organics washed withbrine and dried over MgSO₄. The volatiles were removed under reducedpressure, then the residue purified by silica gel column chromatography(Biotage Isolera, SiO₂ cartridge, 20-100% EtOAc in petroleum benzine40-60° C.) to give the title compound A33 as a white solid (0.250 g,50%); ¹H NMR (400 MHz, d₆-DMSO) δ 7.61 (dd, J=8.8, 5.5 Hz, 1H), 7.48 (s,1H), 7.25 (dd, J=9.8, 3.1 Hz, 1H), 7.07 (td, J=8.6, 3.2 Hz, 1H), 7.02(s, 1H), 3.58 (s, 2H).

(b) 2-(5-Fluoro-2-((trimethylsilyl)ethynyl)phenyl)acetamide (A34)

Under inert conditions a suspension of2-(2-bromo-5-fluorophenyl)acetamide (A33) (0.242 g, 1.04 mmol),PdCl₂(PPh₃)₂ (0.037 g, 0.052 mmol), t-Bu₃PH.BF₄ (0.015 g, 0.052 mmol),CuI (0.010 g, 0.052 mmol) and (trimethylsilyl)acetylene (0.177 mL, 1.25mmol) in anhydrous DMF (9 mL) was degassed with nitrogen for 10 minutes.Et₃N (3 mL) was added and the resulting mixture was stirred at 65° C.under nitrogen for 16 hours. The volatiles were removed under reducedpressure, then the residue adsorbed onto silica gel and purified bycolumn chromatography (Biotage Isolera, SiO₂ cartridge, 0-50% EtOAc inpetroleum benzine 40-60° C.) to give the title compound A34 as a tancoloured solid (0.242 g, 93%); ¹H NMR (400 MHz, d₆-DMSO) δ 7.46 (dd,J=8.6, 5.9 Hz, 1H), 7.38 (s, 1H), 7.15 (dd, J=10.0, 2.7 Hz, 1H), 7.08(td, J=8.6, 2.7 Hz, 1H), 6.99 (s, 1H), 3.60 (s, 2H), 0.23 (s, 9H).

(c) 2-(2-Ethynyl-5-fluorophenyl)acetamide (A35)

To a solution of 2-(5-fluoro-2-((trimethylsilyl)ethynyl)phenyl)acetamide(A34) (0.239 g, 0.958 mmol) in DCM (10 mL) at 0° C. was added TBAF (1.0M in THF; 1.44 mL, 1.44 mmol). The resulting mixture was stirred at 0°C. for 10 minutes, then poured into water (50 mL). The organic phase wasseparated and the aqueous layer was extracted with DCM (2×50 mL). Thecombined organic layers were washed with brine, dried (MgSO₄) and thevolatiles removed in vacuo. The residue was adsorbed onto silica gelthen purified by column chromatography (Biotage Isolera, SiO₂, O-100%EtOAc in petroleum benzine 40-60° C.) to give the title compound A35 asa white solid (0.114 g, 67%); ¹H NMR (400 MHz, d₆-DMSO) δ 7.50 (dd,J=8.6, 5.9 Hz, 1H), 7.44 (s, 1H), 7.17 (dd, J=10.0, 2.7 Hz, 1H), 7.10(td, J=8.6, 2.8 Hz, 1H), 6.99 (s, 1H), 4.32 (s, 1H), 3.61 (s, 2H).LCMS-A: rt 4.843 min; m/z 178 [M+H]⁺.

(d) tert-Butyl4-(4-((4-((2-(2-amino-2-oxoethyl)-4-fluorophenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A36)

A suspension of 2-(2-ethynyl-5-fluorophenyl)acetamide (A35) (0.114 g,0.643 mmol), tert-butyl4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(K5) (0.267 g, 0.585 mmol), PdCl₂(PPh₃)₂ (0.021 g, 0.029 mmol),t-Bu₃PH.BF₄ (8 mg, 0.03 mmol) and CuI (6 mg, 0.03 mmol) in anhydrous DMF(4 mL) was degassed with nitrogen for 10 minutes. Et₃N (1 mL) was addedand the resulting mixture was heated under microwave irradiation at 120°C. for 20 minutes. The volatiles were removed under reduced pressure,then the residue adsorbed onto silica gel and purified by columnchromatography (Biotage Isolera, SiO₂ cartridge, 0-100% EtOAc inpetroleum benzine 40-60° C.) to give the title compound A36 as a yellowsolid (0.198 g, 57%); ¹H NMR (400 MHz, d₆-DMSO) δ 10.41 (s, 1H), 8.81(s, 1H), 7.69-7.62 (m, 3H), 7.47 (s, 1H), 7.31-7.19 (m, 4H), 7.07 (s,1H), 4.05 (s, 2H), 3.72 (s, 2H), 2.80 (s, 2H), 2.69-2.59 (m, 1H), 1.74(d, J=13.5 Hz, 2H), 1.55-1.44 (m, 2H), 1.42 (s, 9H). LCMS-A: rt 6.554min; m/z 596 [M−H]⁻.

(e) tert-Butyl4-(4-((4-(2-(2-amino-2-oxoethyl)-4-fluorophenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A37)

A suspension of 10% Pd/C (0.175 g) and tert-butyl4-(4-((4-((2-(2-amino-2-oxoethyl)-4-fluorophenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A36) (0.191 g, 0.320 mmol) in DMF (10 mL) and Et₃N (1 mL) was stirredunder an atmosphere of hydrogen for 16 hours. The resulting mixture wasdiluted with EtOAc (60 mL), filtered through Celite and the volatileswere removed under reduced pressure. The residue was adsorbed ontosilica gel, then purified by column chromatography (Biotage Isolera,SiO₂ cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give thetitle compound A37 as a yellow solid (0.168 g, 87%); ¹H NMR (400 MHz,d₆-DMSO) δ 10.14 (s, 1H), 8.65 (s, 1H), 7.65 (d, J=8.6 Hz, 2H), 7.48 (s,1H), 7.23-7.15 (m, 3H), 7.08 (dd, J=10.2, 2.8 Hz, 1H), 7.00 (td, J=8.4,2.7 Hz, 2H), 4.07 (d, J=11.8 Hz, 2H), 3.50 (s, 2H), 3.13-3.04 (m, 2H),3.04-2.95 (m, 2H), 2.79 (brs, 2H), 2.69-2.57 (m, 1H), 1.74 (d, J=12.9Hz, 2H), 1.54-1.43 (m, 2H), 1.42 (s, 9H). LCMS-A: rt 6.612 min; m/z 602[M+H]⁺.

(f)2-(5-Fluoro-2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (9)

TFA (0.825 mL, 10.8 mmol) was added to a solution of tert-butyl4-(4-((4-(2-(2-amino-2-oxoethyl)-4-fluorophenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A37) (0.162 g, 0.269 mmol) in DCM (20 mL) under nitrogen and theresulting solution stirred for 24 hours at room temperature. Thevolatiles were removed in vacuo and the residue was taken up in MeOH andloaded onto an SCX cartridge (10 g). The column was eluted with 5 columnvolumes of MeOH and then 6 column volumes of 5% v/v aqueous ammonia inMeOH. The volatiles from the ammoniacal eluent were evaporated underreduced pressure to give the title compound 9 as a yellow solid (0.117g, 87%); ¹H NMR (400 MHz, d₆-DMSO) δ 10.12 (s, 1H), 8.65 (s, 1H), 7.64(d, J=8.6 Hz, 2H), 7.48 (s, 1H), 7.23-7.13 (m, 3H), 7.08 (dd, J=10.2,2.8 Hz, 1H), 7.04-6.95 (m, 2H), 3.50 (s, 2H), 3.14-2.95 (m, 6H),2.63-2.52 (m, 3H), 1.67 (d, J=10.8 Hz, 2H), 1.49 (qd, J=12.4, 3.9 Hz,2H). LCMS-A: rt 4.853 min; m/z 502 [M+H]⁺.

Example 10 Synthesis of2-(5-fluoro-2-(2-(2-((4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(10)

Formaldehyde (37 wt. % in H₂O; 29 μL, 0.39 mmol) was added to asuspension of2-(5-fluoro-2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (9) (0.065 g, 0.13 mmol) in MeOH (8 mL) underan atmosphere of nitrogen. The resulting mixture was stirred for 10minutes at room temperature then sodium triacetoxyborohydride (0.110 g,0.518 mmol) was added in one portion and stirring continued for 3 hoursThe volatiles were removed in vacuo, then the residue was partitionedbetween EtOAc (20 mL) and saturated aqueous NaHCO₃ (20 mL). The layerswere separated and the aqueous layer was extracted with EtOAc (2×20 mL).The combined organic layers were washed with brine (20 mL) and driedover Na₂SO₄. The volatiles were removed under reduced pressure to yieldthe title compound 10 as an off-white solid (58 mg, 87%); ¹H NMR (400MHz, d₆-DMSO) δ 10.13 (s, 1H), 8.65 (s, 1H), 7.64 (d, J=8.6 Hz, 2H),7.49 (s, 1H), 7.22-7.16 (m, 3H), 7.08 (dd, J=10.2, 2.8 Hz, 1H),7.04-6.95 (m, 2H), 3.50 (s, 2H), 3.12-3.04 (m, 2H), 3.04-2.95 (m, 2H),2.87 (d, J=11.3 Hz, 2H), 2.46-2.36 (m, 1H), 2.20 (s, 3H), 2.02-1.92 (m,2H), 1.76-1.58 (m, 4H). LCMS-A: rt 4.867 min; m/z 516 [M+H]⁺.

Example 11 Synthesis of2-(2-(2-(2-((3-methyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (11)

(a) tert-Butyl4-(2-methyl-4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (A38)

A suspension of N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacolester (0.29 g, 0.93 mmol), 1-bromo-2-methyl-4-nitrobenzene (0.20 g, 0.93mmol), PdCl₂(PPh₃)₂ (0.03 g, 0.05 mmol) and 3 M aqueous Na₂CO₃ (0.93 mL,2.8 mmol) in 1,4-dioxane (10 mL) was degassed with nitrogen for 10minutes then heated at reflux for 16 hours. The resulting mixture wasconcentrated under reduced pressure and purified using silica gel columnchromatography (Biotage Isolera, SiO₂ cartridge, 0-30% EtOAc inpetroleum benzine 40-60° C.) to give the title compound A38 (0.25 g,83%); ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J=2.4 Hz, 1H), 8.03-7.98 (m,1H), 7.22 (d, J=8.4 Hz, 1H), 5.63 (s, 1H), 4.09-4.04 (m, 2H), 3.64 (t,J=5.6 Hz, 2H), 2.38 (s, 3H), 2.35 (s, 2H), 1.51 (s, 9H).

(b) tert-Butyl 4-(4-amino-2-methylphenyl)piperidine-1-carboxylate (A39)

To a solution of tert-butyl4-(2-methyl-4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (A38)(211 mg, 0.663 mmol) in DMF (7.5 mL) was added a slurry of 10% Pd/C (100mg) in DMF (0.5 mL) and the resulting mixture was stirred for 16 hoursunder a hydrogen atmosphere at room temperature. The resulting mixturewas filtered through Celite then the volatiles were removed underreduced pressure. The residue was purified by silica gel columnchromatography (Biotage Isolera, SiO₂ cartridge, 0-60% EtOAc inpetroleum benzine 40-60° C.) to give the title compound A39 as a paleorange solid (185 mg, 96%); ¹H NMR (400 MHz, CDCl₃) δ 6.95 (d, J=8.0 Hz,1H), 6.56-6.48 (m, 2H), 3.51 (s, 2H), 2.88-2.65 (m, 3H), 2.26 (s, 3H),1.74-1.66 (m, 2H), 1.63-1.51 (m, obscured by solvent), 1.48 (s, 9H).

(c) tert-Butyl4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylphenyl)piperidine-1-carboxylate(A40)

Zinc(II) chloride (1.0 M in Et₂O; 0.661 mL, 0.661 mmol) was added to asolution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.132 g, 0.606mmol) in 1:1 DCE/t-BuOH (5 mL) at 0° C. under nitrogen. The resultingmixture was stirred for 1 hour at 0° C. then tert-butyl4-(4-amino-2-methylphenyl)piperidine-1-carboxylate (A39) (0.160 g, 0.551mmol) in 1:1 DCE/t-BuOH (5 mL) was added. A solution of Et₃N (840 μL,0.606 mmol) in 1:1 DCE/t-BuOH (5 mL) at 0° C. was then added and theresulting mixture was vigorously stirred for a further 30 minutes at 0°C. then at room temperature for 16 hours. The volatiles were removed invacuo to afford a brown residue which was purified by silica gel columnchromatography (Biotage Isolera, 25 g SiO₂ cartridge, 0-50% EtOAc inpetroleum benzine 40-60° C.) to yield a pale yellow solid. The solid wassuspended in MeOH (10 mL) and water (10 mL) and the resulting suspensionfiltered to give the title compound A40 as a white solid (0.231 g, 89%);¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.27(brs, 1H), 7.24 (d, J=2.3 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 4.32-4.04 (m,2H), 2.79-2.73 (m, 3H), 2.30 (s, 3H), 1.67 (d, J=13.0 Hz, 2H), 1.62-1.45(m, obscured), 1.42 (s, 9H). LCMS-A: rt 6.895 min; m/z 469.1 [M−H]⁻.

(d) tert-Butyl4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylphenyl)piperidine-1-carboxylate(A41)

A solution of methyl 2-(2-ethynylphenyl)acetate (K1) (0.103 g, 0.589mmol) in DMF (1.5 mL) and Et₃N (0.273 mL, 1.96 mmol) were added to asuspension of tert-butyl4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylphenyl)piperidine-1-carboxylate(A40) (0.231 g, 0.491 mmol), PdCl₂(PPh₃)₂ (0.052 g, 0.074 mmol), CuI(0.014 g, 0.074 mmol) and PPh₃ (0.013 g, 0.049 mmol) in DMF (2 mL). Theresulting mixture was heated under microwave irradiation at 120° C. for15 minutes, then diluted with EtOAc and passed through a plug of Celite,washing with EtOAc (60 mL). The filtrate was washed with water (50 mL)and the aqueous layer was extracted with EtOAc (2×50 mL). The combinedorganics were washed with water (50 mL), brine (50 mL) and dried(Na₂SO₄). The volatiles were removed in vacuo and the residue waspurified by silica gel column chromatography (Biotage Isolera, 25 g SiO₂cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to give the titlecompound A41 as a yellow oil (0.248 g, 83%); ¹H NMR (400 MHz, CDCl₃) δ8.62 (s, 1H), 7.68 (dd, J=7.6, 0.9 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H),7.45-7.40 (m, 1H), 7.39-7.29 (m, 4H), 7.18 (d, J=8.4 Hz, 1H), 4.38-4.21(m, 2H), 3.96 (s, 2H), 3.70 (s, 3H), 2.92-2.71 (m, 3H), 2.38 (s, 3H),1.75 (d, J=12.7 Hz, 2H), 1.69-1.54 (m, peak obscured), 1.49 (s, 9H).LCMS-A: rt 6.992 min; m/z 609.1 [M+H]⁺.

(e) tert-Butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylphenyl)piperidine-1-carboxylate(A42)

A solution of tert-butyl4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylphenyl)piperidine-1-carboxylate(A41) (0.248 g, 0.407 mmol) in EtOH (10 mL) was added to a solution of10% Pd/C (53% water; 0.680 g) in DMF (6 mL). The resulting mixture wasstirred at room temperature for 16 hours under an atmosphere of hydrogenthen filtered through a pad of Celite, washing with EtOAc (80 mL). Thevolatiles were removed in vacuo to afford a yellow oil which waspurified by silica gel column chromatography (Biotage Isolera, 25 g SiO₂cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to yield thetitle compound A42 as a clear oil (0.196 g, 79%); ¹H NMR (400 MHz,CDCl₃) δ 8.53 (s, 1H), 7.61 (s, 1H), 7.51 (dd, J=7.9, 1.5 Hz, 1H), 7.39(d, J=2.2 Hz, 1H), 7.29-7.19 (m, obscured by solvent), 7.17 (d, J=8.4Hz, 1H), 4.42-4.18 (m, 2H), 3.75 (s, 2H), 3.67 (s, 3H), 3.19-3.03 (m,4H), 2.90-2.73 (m, 3H), 2.37 (s, 3H), 1.75 (d, J=12.6 Hz, 2H), 1.62 (m,2H), 1.50 (s, 9H). LCMS-A: rt 7.094 min; m/z 613.2 [M+H]⁺.

(f) tert-Butyl4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylphenyl)piperidine-1-carboxylate(A43)

LiOH.H₂O (41.0 mg, 0.960 mmol) was added to a solution of tert-butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylphenyl)piperidine-1-carboxylate(A42) (0.196 g, 0.320 mmol) in THF (7 mL), water (1.5 mL) and MeOH (1mL) and the resulting mixture stirred at room temperature for 19 hours.The volatiles were removed in vacuo, then the residue was partitionedbetween EtOAc (50 mL) and saturated aqueous NaHCO₃ (50 mL). The layerswere separated and the aqueous layer was extracted with EtOAc (2×50 mL).The combined organic layers were washed with brine (50 mL), dried overMgSO₄ and the volatiles removed under reduced pressure. The residue wasdissolved in dry THF (6 mL) and dry DMF (1 mL) under an atmosphere ofnitrogen then HOBt (0.056 g, 0.41 mmol), EDCl.HCl (0.079 g, 0.41 mmol)and DIPEA (0.28 mL, 1.3 mmol) were added. After 10 minutes ammoniumcarbonate (0.15 g, 1.6 mmol) was added in one portion and the resultingmixture stirred at room temperature for 19 hours. The volatiles wereremoved in vacuo and the residue was partitioned between EtOAc (65 mL)and saturated NaHCO₃ (65 mL). The aqueous layer was extracted with EtOAc(2×50 mL) then the combined organic layers were washed with brine (50mL) and dried over MgSO₄. The solvent was removed in vacuo and theresidue purified by silica gel column chromatography (Biotage Isolera,25 g SiO₂ cartridge, 0-80% EtOAc in petroleum benzine 40-60° C.) to givethe title compound A43 as a white solid (0.16 g, 84%); ¹H NMR (400 MHz,CDCl₃) δ 8.49 (s, 1H), 8.20 (s, 1H), 7.46 (dd, J=8.4, 2.0 Hz, 1H), 7.37(d, J=1.9 Hz, 1H), 7.28-7.18 (m, obscured by solvent), 7.13 (d, J=8.4Hz, 1H), 6.33 (s, 1H), 5.68 (s, 1H), 4.40-4.16 (m, 2H), 3.68 (s, 2H),3.17-2.95 (m, 4H), 2.91-2.68 (m, 3H), 2.34 (s, 3H), 1.73 (d, J=12.3 Hz,2H), 1.68-1.53 (m, 2H), 1.50 (s, 9H). LCMS-A: rt 6.670 min; m/z 598.1[M+H]⁺.

(g)2-(2-(2-(2-((3-methyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(11)

TFA (1 mL) was added to a stirred solution of tert-butyl4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylphenyl)piperidine-1-carboxylate(A43) (0.16 g, 0.27 mmol) in DCM (4 mL) and the resulting solution wasstirred at room temperature for 16 hours. The volatiles were removed invacuo and the residue was partitioned between EtOAc (10 mL) and 2 Maqueous NaOH (10 mL). The aqueous layer was extracted with EtOAc (2×10mL) then and the combined organic layers were washed with water (10 mL),brine (10 mL) and dried over MgSO₄. The volatiles were removed in vacuoto give a pale yellow solid. The solid was suspended in cyclohexane andthe resulting suspension filtered to give the title compound 11 as awhite solid (0.085 g, 64%); ¹H NMR (400 MHz, d₄-MeOH) δ 8.52 (s, 1H),7.54 (dd, J=8.4, 2.2 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.29-7.23 (m, 1H),7.23-7.15 (m, 4H), 3.67 (s, 2H), 3.23-3.11 (m, 4H), 3.10-3.01 (m, 2H),2.91 (tt, J=11.7, 3.8 Hz, 1H), 2.80 (td, J=12.3, 2.8 Hz, 2H), 2.35 (s,3H), 1.84-1.59 (m, 4H). LCMS-A: rt 4.962 min; m/z 498.3 [M+H]⁺.

Example 12 Synthesis of 2-(2-(2-(2-((3-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(12)

Formaldehyde (37 wt. % in H₂O; 0.040 mL, 0.50 mmol) was added to asuspension of2-(2-(2-(2-((3-methyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(11) (0.035 g, 0.070 mmol) in MeOH (5 mL) under an atmosphere ofnitrogen. Sodium triacetoxyborohydride (0.19 g, 0.10 mmol) was added inone portion and the resulting mixture stirred at room temperature for 3hours. The volatiles were removed in vacuo and the residue waspartitioned between EtOAc (10 mL) and saturated aqueous NaHCO₃ (10 mL).Solid NaHCO₃ was added until the formation of gas ceased then the layerswere separated and the aqueous layer was extracted with EtOAc (2×100mL). The combined organic layers were washed with water (10 mL), brine(10 mL) and dried over Na₂SO₄. The volatiles were removed under reducedpressure to yield the title compound 12 as a white solid (0.032 g, 89%);¹H NMR (400 MHz, d₄-MeOH) δ 8.52 (s, 1H), 7.53 (dd, J=8.4, 2.3 Hz, 1H),7.44 (d J=2.2 Hz, 1H), 7.28-7.22 (m, 1H), 7.24-7.15 (m, 4H), 3.67 (s,2H), 3.20-3.11 (m, 2H), 3.11-2.95 (m, 4H), 2.81-2.70 (m, 1H), 2.35 (s,3H), 2.34 (s, 3H), 2.28-2.13 (m, 2H), 1.87-1.70 (m, 4H). LCMS-A: rt4.908 min; m/z 512.3 [M+H]⁺.

Example 13 Synthesis of2-(2-(2-(2-((6-(piperidin-4-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(13)

(a) tert-Butyl4-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate(A44)

A 1.0 M ZnCl₂ solution in Et₂O (2.16 mL, 2.16 mmol) was added cautiouslyto a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (411 mg,1.89 mmol) in 1:1 t-BuOH:DCE (100 mL) at room temperature and theresulting mixture stirred at room temperature for 20 minutes. tert-Butyl4-(5-aminopyridin-2-yl)piperidine-1-carboxylate (K4) (500 mg, 1.80 mmol)was added followed by Et₃N (0.30 mL, 2.16 mmol) then stirring wascontinued for 44 hours at room temperature. The volatiles were removedin vacuo and the residue was suspended in water (250 mL). The resultingsuspension was sonicated for 10 minutes then filtered, washing thefilter cake with water (2×100 mL). The filter cake was adsorbed ontosilica gel and purified by column chromatography (Biotage Isolera, 40 gSiO₂ cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give thetitle compound A44 as an off white solid (346 mg, 42%); ¹H NMR (400 MHz,d₆-DMSO) δ 10.74 (s, 1H), 8.81 (s, 1H), 8.73 (d, J=2.4 Hz, 1H), 8.00(dd, J=8.5, 2.5 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 4.05 (d, J=11.8 Hz,2H), 2.82 (m, 3H), 1.81 (d, J=11.1 Hz, 2H), 1.55 (m, 2H), 1.41 (s, 9H).LCMS-A: rt 5.949 min; m/z 458 [M+H]⁺.

(b) tert-Butyl4-(5-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate(A45)

A suspension of tert-butyl4-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate(A44) (340 mg, 0.74 mmol), CuI (7 mg, 0.04 mmol), PPh₃ (10 mg, 0.04mmol) and Et₃N (207 μL, 1.49 mmol) in DMF (2.5 mL) was sonicated for 5minutes. PdCl₂(PPh₃)₂ (26 mg, 0.04 mmol) and methyl2-(2-ethynylphenyl)acetate (K1) (194 mg, 1.11 mmol) in DMF (1 mL) wereadded and the resulting mixture degassed with nitrogen for 5 minutesbefore heating under microwave irradiation at 120° C. for 20 minutes.The resulting mixture was adsorbed on silica gel and purified by columnchromatography (Biotage Isolera, 40 g SiO₂ cartridge, 0-100% EtOAc inhexanes) to give a brown oil that was taken up in DMF (25 mL) and Et₃N(2 mL) before 10% Pd/C (53% water; 75 mg) was added. The resultingmixture was stirred at room temperature for 44 hours under a hydrogenatmosphere then filtered through Celite, washing with EtOAc (200 mL).Activated charcoal (ca. 2.5 g) was added to the filtrate and theresulting suspension stirred at room temperature for 4 hours beforefiltration through Celite, washing with EtOAc (100 mL). The filtrate waswashed with water (100 mL), brine (100 mL), dried (Na₂SO₄) andconcentrated under reduced pressure to give a brown oil. A suspension of10% Pd/C (53% water; 200 mg) in DMF (100 mL) and Et₃N (10 mL) was addedand the resulting mixture stirred under a hydrogen atmosphere at roomtemperature for 4.5 days. The resulting mixture was filtered throughCelite, washing with EtOAc (250 mL) then the combined filtrates werewashed with water (3×100 mL) then brine (3×100 mL). The organic layerwas dried (Na₂SO₄), filtered and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (BiotageIsolera, 40 g SiO₂ cartridge, 0-100% EtOAc in petroleum benzine 40-60°C.) to give the title compound A45 as a yellow oil (96 mg, 21%); ¹H NMR(400 MHz, CDCl₃) δ 8.65 (d, J=2.4 Hz, 1H), 8.55 (d, J=0.5 Hz, 1H), 8.14(dd, J=8.5, 2.7 Hz, 1H), 7.55 (s, 1H), 7.25-7.18 (m, 4H), 7.16 (d, J=8.5Hz, 1H), 4.26 (s, 2H), 3.74 (s, 2H), 3.68 (s, 3H), 3.11 (s, 4H),2.88-2.79 (m, 3H), 1.92 (d, J=12.0 Hz, 2H), 1.77-1.64 (m, 2H), 1.47 (s,9H). LCMS-A: rt 6.137 min; m/z 600 [M+H]⁺.

(c)2-(2-(2-(2-((6-(1-(tert-Butoxycarbonyl)piperidin-4-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid (A46)

LiOH.H₂O (297 mg, 7.1 mmol) was added to a stirred solution oftert-butyl4-(5-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate(A45) (85 mg, 0.14 mmol) in H₂O (2 mL) and THF (20 mL) and the resultingmixture heated at 40° C. for 18 hours. The volatiles were removed invacuo and the residue was partitioned between EtOAc (100 mL), andaqueous 2 M HCl (50 mL). The layers were separated and the organicswashed with water (100 mL), brine (50 mL) and dried over MgSO₄. Thevolatiles were removed in vacuo to give the title compound A46 as anorange foam (74 mg, 89%); ¹H NMR (400 MHz, d₄-MeOH) δ 9.00 (d, J=1.8 Hz,1H), 8.66 (s, 1H), 8.36 (dd, J=8.7, 2.6 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H),7.28-7.10 (m, 4H), 4.25 (d, J=13.4 Hz, 2H), 3.72 (s, 2H), 3.19-3.09 (m,4H), 3.07-2.83 (m, 3H), 1.94 (d, J=12.7 Hz, 2H), 1.72 (m, 2H), 1.48 (s,9H). LCMS-A: rt 5.707 min; m/z 586 [M+H]⁺.

(d) tert-Butyl4-(5-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate(A47)

HOBt (50 mg, 0.37 mmol), EDCl.HCl (78 mg, 0.41 mmol) and DIPEA (0.11 mL,0.63 mmol) were added to a stirred solution of2-(2-(2-(2-((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)aceticacid (A46) (74 mg, 0.13 mmol) in dry DMF (5 mL) under an atmosphere ofnitrogen. After 10 minutes ammonium carbonate (121 mg, 1.26 mmol) wasadded in one portion and the resulting mixture was stirred for 18 hoursat room temperature. The volatiles were removed in vacuo and the residuewas partitioned between EtOAc (10 mL) and saturated aqueous NaHCO₃ (10mL). The aqueous layer was extracted with EtOAc (2×10 mL) then thecombined organic layers were washed with brine (10 mL) and dried overNa₂SO₄. The volatiles were removed in vacuo and the residue purified bysilica gel column chromatography (Biotage Isolera, 40 g SiO₂ cartridges,0-100% EtOAc in petroleum benzine 40-60° C. followed by 0-25% MeOH inEtOAc) to give the title compound A47 as clear oil (58 mg, 78%); ¹H NMR(400 MHz, CDCl₃) δ 8.83 (s, 1H), 8.54 (s, 1H), 7.97 (s, 1H), 7.80 (s,1H), 7.30-7.22 (m, 4H), 7.17 (d, J=8.5 Hz, 1H), 5.78 (s, 1H), 5.62 (s,1H), 4.25 (s, 2H), 3.74 (s, 2H), 3.11 (s, 4H), 2.83 (m, 3H), 1.92 (d,J=12.3 Hz, 2H), 1.79-1.60 (m, 2H, peak obscured), 1.48 (s, 9H). LCMS-A:rt 5.549 min; m/z 585 [M+H]⁺.

(e)2-(2-(2-(2-((6-(Piperidin-4-yl)pyridin-3-yl)-amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(13)

TFA (0.5 mL) was added to a solution of tert-butyl4-(5-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate(A47) (58 mg, 0.099 mmol) in DCM (5 mL) and the resulting solutionstirred for 18 hours at room temperature. The volatiles were evaporatedunder reduced pressure and the residue partitioned between 2 M aqueousNaOH (10 mL) and EtOAc (25 mL). The organic layer was separated andwashed with water (25 mL), brine (25 mL), dried (Na₂SO₄) andconcentrated under reduced pressure to give the title compound 13 as awhite solid (41 mg, 85%); ¹H NMR (400 MHz, d₄-MeOH) δ 8.78 (d, J=2.1 Hz,1H), 8.61 (d, J=0.6 Hz, 1H), 8.19 (dd, J=8.6, 2.6 Hz, 1H), 7.31 (d,J=8.5 Hz, 1H), 7.26 (d, J=6.3 Hz, 1H), 7.24-7.15 (m, 3H), 3.67 (s, 2H),3.22-3.15 (m, 4H), 3.14-3.05 (m, 2H), 2.90-2.70 (m, 3H), 1.93 (d, J=13.9Hz, 2H), 1.75 (m, 2H). LCMS-A: rt 4.552 min; m/z 485 [M+H]⁺.

Example 14 Synthesis of2-(2-(2-(2-((6-(1-methylpiperidin-4-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(14)

Formaldehyde (37 wt. % in H₂O; 0.012 mL, 0.17 mmol) was added to asolution of2-(2-(2-(2-((6-(piperidin-4-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(13) (27 mg, 0.056 mmol) in MeOH (2 mL) under an atmosphere of nitrogen.The resulting mixture was stirred for 15 minutes at room temperaturebefore sodium triacetoxyborohydride (47 mg, 0.22 mmol) was added in oneportion and stirring was continued at room temperature for 18 hours. Thevolatiles were removed in vacuo and the residue was partitioned betweenEtOAc (50 mL) and saturated aqueous NaHCO₃ (50 mL). The layers wereseparated and the aqueous layer was extracted with EtOAc (2×25 mL). Thecombined organic layers were washed with water (25 mL), brine (25 mL)then dried over Na₂SO₄. The solvent was removed under reduced pressureto give the title compound 14 as a white solid (25 mg, 90%); ¹H NMR (400MHz, d₄-MeOH) δ 8.77 (d, J=2.4 Hz, 1H), 8.60 (s, 1H), 8.18 (dd, J=8.6,2.6 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.26 (d, J=6.3 Hz, 1H), 7.21-7.15(m, 3H), 3.67 (s, 2H), 3.20-3.14 (m, 2H), 3.14-3.08 (m, 2H), 3.04 (d,J=11.7 Hz, 2H), 2.71 (tt, J=11.9, 3.9 Hz, 1H), 2.35 (s, 3H), 2.21 (td,J=12.0, 2.5 Hz, 2H), 1.96 (d, J=11.0 Hz, 2H), 1.92-1.80 (m, 2H). LCMS-A:rt 4.635 min; m/z 499 [M+H]⁺.

Example 15 Synthesis of2-(4-fluoro-2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(15)

Methyl 2-(2-bromo-4-fluorophenyl)acetate (A48)

Sulfuric acid (1.50 mL) was added cautiously to a solution of2-bromo-4-fluorophenylacetic acid (1.00 g, 4.29 mmol) in MeOH (25 mL)and the resulting mixture stirred overnight at room temperature.Saturated aqueous Na₂CO₃ solution was added until the pH of the mixturewas 14, then the aqueous layer was extracted with DCM (2×100 mL). Thecombined organics were dried over MgSO₄ then the volatiles were removedin vacuo to yield the title compound A48 as a clear oil (1.00 g, 94%);¹H NMR (400 MHz, CDCl₃) δ 7.34 (dd, J=8.2, 2.6 Hz, 1H), 7.29 (dd, J=8.5,6.0 Hz, 1H), 7.03 (td, J=8.3, 2.6 Hz, 1H), 3.79 (s, 2H), 3.74 (s, 3H).LCMS-A: rt 5.911 min.

(b) Methyl 2-(4-fluoro-2-((trimethylsilyl)-ethynyl)phenyl)acetate (A49)

A suspension of (trimethylsilyl)acetylene (0.696 g, 7.08 mmol), methyl2-(2-bromo-4-fluorophenyl)acetate (A48) (0.500 g, 2.02 mmol), PPh₃(0.053 g, 0.202 mmol), CuI (39 mg, 0.202 mmol), Et₃N (1.41 mL, 10.1mmol) and PdCl₂(PPh₃)₂ (0.142 g, 0.202 mmol) in THF (25 mL) was heatedat 35° C. for 16 hours. The resulting mixture was adsorbed onto silicagel and purified using column chromatography (Biotage Isolera, 40 g SiO₂cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to yield thetitle compound A49 as a clear oil (0.212 g, 40%); LCMS-A: rt 6.830 min.

(c) Methyl 2-(2-ethynyl-4-fluorophenyl)acetate (A50)

A solution of TBAF (1.0 M in THF; 2.0 mL, 2.0 mmol) was added to astirred solution of methyl2-(4-fluoro-2-((trimethylsilyl)ethynyl)phenyl)acetate (A49) (0.212 g,0.802 mmol) in DCM (5 mL). After 2 minutes the resulting mixture wasdiluted with water (100 mL) and DCM (50 mL). The organic fraction wasseparated and adsorbed onto silica gel then purified using columnchromatography (Biotage Isolera, 12 g SiO₂ Cartridge, 0-20% EtOAc inpetroleum benzine 40-60° C.) to give the title compound A50 as a brownoil (0.106 g, 69%); ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.26 (m, 1H), 7.23(dd, J=9.0, 2.8 Hz, 1H), 7.06 (m, 1H), 3.84 (s, 2H), 3.73 (s, 3H), 3.33(s, 1H). LCMS-A: rt 5.838 min; m/z 193 [M+H]⁺.

(d) tert-Butyl4-(4-((4-((5-fluoro-2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A51)

A suspension of tert-butyl4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(K5) (0.252 g, 0.552 mmol), methyl 2-(2-ethynyl-4-fluorophenyl)acetate(A50) (0.106 g, 0.552 mmol), PPh₃ (0.007 g, 0.03 mmol), CuI (0.005 g,0.03 mmol) and PdCl₂(PPh₃)₂ (0.019 g, 0.028 mmol) in DMF (3 mL) and Et₃N(1.0 mL) was heated under microwave irradiation for 20 minutes at 120°C. The resulting mixture was diluted with EtOAc (100 mL) then washedwith water (100 mL), brine (25 mL) and dried over MgSO₄. The volatileswere evaporated in vacuo and the residue was adsorbed onto silica geland purified using column chromatography (Biotage Isolera, 40 g SiO₂cartridge, 0-80% EtOAc in petroleum benzine 40-60° C.) to give the titlecompound A51 as a yellow solid (0.158 g, 47%); ¹H NMR (400 MHz, CDCl₃) δ8.64 (d, J=1.0 Hz, 1H), 7.75 (s, 1H), 7.62-7.55 (m, 2H), 7.38-7.27 (m,2H), 7.25-7.19 (m, 2H), 7.14 (td, J=8.3, 2.7 Hz, 1H), 4.36-4.20 (m, 2H),3.92 (s, 2H), 3.72 (s, 3H), 2.82 (t, J=12.8 Hz, 2H), 2.66 (td, J=8.5,4.2 Hz, 1H), 1.89-1.78 (m, 2H), 1.70-1.54 (m, 2H), 1.51 (s, 9H). LCMS-A:rt 1.852 min; m/z 613 [M+H]⁺.

(e) tert-Butyl4-(4-((4-(5-fluoro-2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A52)

A suspension of Pd/C 10% (0.100 g) and tert-butyl4-(4-((4-((5-fluoro-2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A51) (0.158 g, 0.258 mmol) in EtOAc (20 mL) was stirred under ahydrogen atmosphere at room temperature overnight. The resulting mixturewas filtered through a Celite plug, washing with EtOAc (100 mL) then thecombined organic washings were evaporated in vacuo to yield the titlecompound A52 as a yellow oil (0.092 g, 58%); ¹H NMR (400 MHz, CDCl₃) δ8.46 (s, 1H), 7.48 (d, J=8.5 Hz, 2H), 7.17-7.10 (m, 3H), 6.91-6.78 (m,2H), 4.18 (s, 2H), 3.62 (s, 2H), 3.60 (s, 3H), 3.01 (s, 4H), 2.73 (t,J=11.9 Hz, 2H), 2.57 (tt, J=12.0, 3.4 Hz, 1H), 1.75 (d, J=12.8 Hz, 2H),1.54 (qd, J=12.8, 4.2 Hz, 2H), 1.41 (s, 9H). LCMS-A: rt 6.727/6.998 min;m/z 617 [M+H]⁺. (f) Lithium2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-4-fluorophenyl)acetate(A53) LiOH.H₂O (0.063 g, 1.5 mmol) was added to a stirred solution oftert-butyl4-(4-((4-(5-fluoro-2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A52) (0.092 g, 0.15 mmol) in H₂O (0.5 mL) and THF (5 mL) and theresulting mixture heated at 40° C. overnight. The volatiles were removedin vacuo and the residue was taken up in DCM (50 mL). The resultingsolution was washed with saturated aqueous Na₂CO₃ (25 mL) then theaqueous phase was then extracted with DCM (2×25 mL). The organic layerswere combined, dried over MgSO₄ and the volatiles were removed in vacuoto yield the title compound A53 (0.089 g, 98%); LCMS-A: rt 6.596 min;m/z 603 [(M-Li)+H]⁺.

(g) tert-Butyl4-(4-((4-(2-(2-amino-2-oxoethyl)-5-fluorophenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A54)

HOBt (0.024 g, 0.175 mmol) and EDCl.HCl (0.034 g, 0.175 mmol) were addedto a solution of lithium2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-4-fluorophenyl)acetate(A53) (0.089 g, 0.146 mmol) and Et₃N (0.082 mL, 0.585 mmol) in DMF (5mL) and the resulting mixture stirred at 40° C. overnight. Saturatedaqueous NaHCO₃ (25 mL) and DCM (25 mL) were added then the layersseparated and the aqueous phase extracted with CHCl₃ (3×25 mL). Theorganics were combined then the volatiles were evaporated in vacuo. Theresidue was adsorbed onto silica gel and purified using columnchromatography (Biotage Isolera, 12 g SiO₂ cartridge, 0-100% EtOAc inpetroleum benzine 40-60° C.) to yield a clear oil. The oil wastriturated with water and the resulting precipitate collected byfiltration to give the title compound A54 as a white solid (0.065 g,74%); ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J=1.0 Hz, 1H), 7.46 (d, J=8.2Hz, 3H), 7.18-7.09 (m, 3H), 6.95-6.84 (m, 2H), 5.24 (d, J=21.9 Hz, 2H),4.18 (s, 2H), 3.60 (s, 2H), 3.02 (s, 4H), 2.74 (t, J=10.2 Hz, 2H), 2.58(m, 1H), 1.76 (d, J=11.7 Hz, 2H), 1.64-1.51 (m, 2H), 1.42 (s, 9H).LCMS-A: rt 6.477 min; m/z 602 [M+H]⁺.

(h)2-(4-Fluoro-2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(15)

TFA (0.5 mL) was added to a solution of tert-butyl4-(4-((4-(2-(2-amino-2-oxoethyl)-5-fluorophenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A54) (0.065 g, 0.108 mmol) in DCM (5.0 mL) and the resulting mixturestirred at room temperature overnight. The volatiles were removed invacuo to yield an orange oil to which 2 M aqueous NaOH (25 mL) wascautiously added. The resulting suspension was sonicated for 10 minutesthen filtered. The white filter cake was washed with water (50 mL),petroleum benzine 40-60° C. (50 mL) then air dried to yield the titlecompound 15 as a white solid (0.036 g, 66%); ¹H NMR (400 MHz, d₆-DMSO) δ10.13 (s, 1H), 8.66 (s, 1H), 7.65 (d, J=8.6 Hz, 2H), 7.45 (s, 1H), 7.26(dd, J=8.3, 6.2 Hz, 1H), 7.18 (d, J=8.6 Hz, 2H), 7.06-6.96 (m, 2H), 6.94(s, 1H), 3.47 (s, 2H), 3.17-2.95 (m, 6H), 2.56 (m, 3H), 1.67 (d, J=13.6Hz, 2H), 1.49 (qd, J=12.1, 2.8 Hz, 2H). LCMS-A: rt 4.687 min; m/z 502[M+H]⁺.

Example 16 Synthesis of2-(2-(2-(5-methyl-2-((4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(16)

(a)2-(2-(2-(2-((4-(1-(tert-Butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-methylpyrimidin-4-yl)ethyl)phenyl)aceticacid (A55)

To a suspension of methyl2-(2-((2-chloro-5-methylpyrimidin-4-yl)ethynyl)phenyl)acetate (K7) (110mg, 0.366 mmol) in 1,4-dioxane (5 mL) was added tert-butyl4-(4-aminophenyl)piperidine-1-carboxylate (101 mg, 0.366 mmol), Cs₂CO₃(477 mg, 1.46 mmol), Pd₂(dba)₃ (33 mg, 0.037 mmol) and Xantphos (63 mg,0.11 mmol). The resulting suspension was degassed with nitrogen for 5minutes then heated under microwave irradiation for 30 minutes at 120°C. The volatiles were removed under reduced pressure and the residue wasadsorbed onto silica gel and purified by column chromatography (BiotageIsolera, SiO₂ cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) togive a yellow oil. A suspension of 10% Pd/C (100 mg) in DMF (10 mL) andEt₃N (1 mL) was added and the resulting mixture stirred under anatmosphere of hydrogen for 16 hours. EtOAc (60 mL) was added and theresulting mixture filtered through Celite. The filtrate was evaporatedunder reduced pressure and the residue was adsorbed onto silica gel andpurified by column chromatography (Biotage Isolera, SiO₂ cartridges,0-60% EtOAc in petroleum benzine 40-60° C.) to give a yellow oil. Thiswas taken up in THF (7 mL), MeOH (7 mL) and H₂O (1.5 mL) to whichLiOH.H₂O (115 mg, 2.74 mmol) was added. The resulting mixture wasstirred at room temperature overnight then the volatiles were removedunder reduced pressure. The residue was partitioned between EtOAc (50mL) and aqueous HCl (2 M; 50 mL) then the layers were separated. Theaqueous phase was extracted with EtOAc (2×50 mL) then the organics werecombined, washed with brine and dried over MgSO₄. The volatiles wereremoved in vacuo to give the title compound A55 as yellow oil (127 mg,87%); LCMS-A: rt 6.272 min; m/z 531 [M+H]⁺.

(b) tert-Butyl4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A56)

HOBt (49 mg, 0.36 mmol), EDCl.HCl (69 mg, 0.36 mmol) and DIPEA (0.21 mL,1.2 mmol) were added to a stirred solution of2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-methylpyrimidin-4-yl)ethyl)phenyl)aceticacid (A55) (127 mg, 0.239 mmol) in dry THF (6 mL) and dry DMF (1 mL)under an atmosphere of nitrogen. After 10 minutes ammonium carbonate(115 mg, 1.20 mmol) was added in one portion and the resulting mixturewas stirred at room temperature for 24 hours. The volatiles were removedin vacuo then the residue was partitioned between EtOAc (50 mL) andsaturated aqueous NaHCO₃ (50 mL). The layers were separated and theaqueous phase was extracted with EtOAc (2×50 mL). The organic extractswere combined, washed with brine and dried over MgSO₄. The volatileswere removed under reduced pressure and the residue purified by columnchromatography (0-100% EtOAc in petroleum benzine 40-60° C.) to give thetitle compound A56 as an off-white solid (66 mg, 52%); ¹H NMR (400 MHz,d₆-DMSO) δ 9.36 (s, 1H), 8.25-8.16 (m, 1H), 7.74 (d, J=8.7 Hz, 2H), 7.49(s, 1H), 7.28 (m, 1H), 7.25-7.14 (m, 5H), 7.00 (s, 1H), 4.14 (m, 2H),3.56 (s, 2H), 3.17-3.04 (m, 2H), 2.98-2.91 (m, 2H), 2.84 (m, 2H),2.71-2.60 (m, 1H), 2.13 (s, 3H), 1.79 (d, J=11.7 Hz, 2H), 1.59-1.43 (m,11H). LCMS-A: rt 6.078 min; m/z 530 [M+H]⁺.

(c)2-(2-(2-(5-Methyl-2-((4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(16)

TFA (0.37 mL, 4.8 mmol) was added to a solution of tert-butyl4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A56) (64 mg, 0.12 mmol) in DCM (20 mL) under nitrogen and the resultingmixture stirred for 24 hours at room temperature. The volatiles wereremoved in vacuo and the residue was taken up in MeOH and loaded onto anSCX cartridge (10 g). The column was eluted with 5 column volumes ofMeOH and then 5 column volumes of 5% v/v aqueous ammonia in MeOH. Thevolatiles from the ammoniacal filtrate were evaporated under reducedpressure and the resulting solid dried under high vacuum to give thetitle compound 16 as a white solid (36 mg, 69%); ¹H NMR (400 MHz,d₆-DMSO) δ 9.28 (s, 1H), 8.15 (s, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.44 (s,1H), 7.25-7.13 (m, 4H), 7.10 (d, J=8.6 Hz, 2H), 6.93 (s, 1H), 3.50 (s,2H), 3.10-2.98 (m, 4H), 2.94-2.82 (m, 2H), 2.65-2.53 (m, 3H), 2.06 (s,3H), 1.67 (d, J=10.6 Hz, 2H), 1.49 (qd, J=12.4, 3.7 Hz, 2H). LCMS-A: rt4.463 min; m/z 430 [M+H]⁺.

Example 17 Synthesis of2-(2-(2-(2-((4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-4-(trifluoromethyl)phenyl)acetamide(17)

(a) Methyl 2-(2-bromo-4-(trifluoromethyl)phenyl)acetate (A57)

A solution of 2-bromo-4-trifluoromethylphenylacetic acid (2.00 g, 7.07mmol) and concentrated aqueous H₂SO₄ (1 mL) in MeOH (30 mL) was heatedat reflux for 16 hours. The volatiles were removed under reducedpressure then the residue taken up in EtOAc. The resulting solution waswashed with 10% NaHCO₃, dried (MgSO₄) and evaporated under reducedpressure to give the title compound A57 as a clear liquid (2.07 g, 98%);¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J=1.1 Hz, 1H), 7.53 (dd, J=8.0, 1.1Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 3.84 (s, 2H), 3.72 (s, 3H). LCMS-A: rt6.236 min; m/z 297/299 [M+H]⁺.

(b) Methyl2-(4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)phenyl)acetate (A58)

A suspension of methyl 2-(2-bromo-4-(trifluoromethyl)phenyl)acetate(A57) (1.60 g, 5.38 mmol), PdCl₂(PPh₃)₂ (189 mg, 269 μmmol), t-Bu₃PH.BF₄(78.1 mg, 269 μmmol), CuI (51.3 mg, 269 μmol) and TMS-acetylene (1.52mL, 10.8 mmol) in Et₃N (10 mL) and anhydrous, degassed DMF (10 mL) wasstirred at 80° C. for 16 hours. The resulting mixture was adsorbed ontosilica gel and purified using column chromatography (Biotage Isolera,SiO₂ cartridge, 0-10% EtOAc in petroleum benzine 40-60° C.) to give thetitle compound A58 as an orange liquid (1.56 g, 92%); ¹H NMR (400 MHz,CDCl₃) δ 7.73 (d, J=1.1 Hz, 1H), 7.53 (dd, J=8.1, 1.3 Hz, 1H), 7.39 (d,J=8.1 Hz, 1H), 3.87 (s, 2H), 3.71 (s, 3H), 0.26 (s, 9H). LCMS-A: rt6.979 min; m/z 315 [M+H]⁺.

(c) Methyl 2-(2-ethynyl-4-(trifluoromethyl)phenyl)acetate (A59)

TBAF (1.0 M in THF; 7.16 mL, 7.15 mmol) was added to a stirred solutionof methyl2-(4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)phenyl)acetate (A58)(1.50 g, 4.77 mmol) in THF (50 mL) at 0° C. After 5 minutes theresulting mixture was diluted with EtOAc (50 mL) then washed with 10%NaHCO₃ (50 mL). The organic layer was dried (MgSO₄) and evaporated underreduced pressure. The residue was adsorbed onto silica gel and purifiedby column chromatography (Biotage Isolera, SiO₂ cartridge, 0-10% EtOAcin petroleum benzine 40-60° C.) to give the title compound A59 as a darkred liquid (956 mg, 83%); ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J=1.2 Hz,1H), 7.57 (dd, J=8.1, 1.4 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 3.90 (s, 2H),3.72 (s, 3H), 3.36 (s, 1H). LCMS-A: rt 6.099 min; m/z 243.1 [M+H]⁺.

(d) tert-Butyl4-(4-((4-((2-(2-methoxy-2-oxoethyl)-5-(trifluoromethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A60)

A stirred suspension of tert-butyl4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(K5) (0.200 g, 0.438 mmol), PdCl₂(PPh₃)₂ (0.031 g, 0.044 mmol),t-Bu₃PH.BF₄ (0.013 mg, 0.044 mmol), CuI (0.008 g, 0.044 mmol) and methyl2-(2-ethynyl-4-(trifluoromethyl)phenyl)acetate (A59) (0.212 g, 0.875mmol) in anhydrous, degassed DMF (6 mL) and Et₃N (6 mL) was heated at120° C. for 20 minutes under nitrogen. The volatiles were evaporatedunder reduced pressure then the residue adsorbed onto silica gel andpurified by column chromatography (Biotage Isolera, SiO₂ cartridge,0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compoundA60 as a brown solid (0.176 g, 61%); ¹H NMR (400 MHz, CDCl₃) δ 8.64 (s,1H), 7.93 (d, J=0.8 Hz, 1H), 7.67 (dd, J=8.2, 1.3 Hz, 1H), 7.56 (d,J=8.5 Hz, 2H), 7.51-7.49 (m, 2H), 7.23 (d, J=8.5 Hz, 2H), 4.36-4.18 (m,2H), 4.01 (s, 2H), 3.72 (s, 3H), 2.91-2.74 (m, 2H), 2.72-2.58 (m, 1H),1.83 (d, J=12.6 Hz, 2H), 1.64-1.56 (m, 2H), 1.50 (s, 9H). LCMS-A: rt7.227 min; m/z 661 [M−H]⁻.

(e) tert-Butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)-5-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A61)

A suspension of 10% Pd/C (0.050 g) and tert-butyl4-(4-((4-((2-(2-methoxy-2-oxoethyl)-5-(trifluoromethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A60) (0.200 g, 0.302 mmol) in DMF (10 mL) and Et₃N (1 mL) was stirredat room temperature for 16 hours under an atmosphere of hydrogen. Theresulting mixture was filtered through Celite, washing with MeOH. Thevolatiles were removed under reduced pressure then the residue wasadsorbed onto silica gel and purified by column chromatography (BiotageIsolera, SiO₂ cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.;repeated twice) to give the title compound A61 (170 mg, 84%); ¹H NMR(400 MHz, CDCl₃) δ 8.54 (s, 1H), 7.55 (d, J=8.6 Hz, 2H), 7.49 (s, 1H),7.47-7.45 (m, 1H), 7.41 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.5Hz, 2H), 4.37-4.17 (m, 2H), 3.79 (s, 2H), 3.69 (s, 3H), 3.24-3.14 (m,2H), 3.21-3.06 (m, 2H), 2.92-2.72 (m, 2H), 2.71-2.52 (m, 1H), 1.90-1.74(m, 2H), 1.68-1.60 (m, 2H), 1.48 (s, 9H). LCMS-A: rt 7.149 min; m/z 667[M+H]⁺.

(f) tert-Butyl4-(4-((4-(2-(2-amino-2-oxoethyl)-5-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A62)

A suspension of tert-butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)-5-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A61) (0.100 g, 0.150 mmol) and LiOH.H₂O (0.051 g, 1.21 mmol) in MeOH (2mL), water (2 mL) and THF (2 mL) was heated at 40° C. for 16 hours. In aseparate flask, a suspension of tert-butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)-5-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A61) (0.070 g, 0.105 mmol) and LiOH.H₂O (0.036 g, 0.858 mmol) in MeOH(2 mL), water (2 mL) and THF (2 mL) was heated at 40° C. for 16 hours.The resulting mixtures were combined and the volatiles were removedunder reduced pressure. The resulting solid was dissolved in dry DMF (5mL) and dry THF (5 mL) and HOBt (0.053 g, 0.398 mmol), EDCl.HCl (0.061g, 0.398 mmol), DIPEA (0.260 mL, 1.53 mmol) and ammonium carbonate(0.144 g, 1.53 mmol) were added. The resulting mixture was stirred atroom temperature for 16 hours then HOBt (0.053 g, 0.398 mmol), EDCl.HCl(0.061 g, 0.398 mmol), DIPEA (0.260 mL, 1.53 mmol) and ammoniumcarbonate (0.144 g, 1.53 mmol) were added and stirring was continuedovernight. The resulting mixture was diluted with EtOAc, then washedwith 10% aqueous NaHCO₃. The organic layer was dried (MgSO₄) and thevolatiles were removed in vacuo. The resulting solid was adsorbed ontosilica gel then purified by column chromatography (Biotage Isolera, SiO₂cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the titlecompound A62 as a yellow solid (0.086 g, 43%); ¹H NMR (400 MHz, CDCl₃) δ8.54 (s, 1H), 7.55-7.47 (m, 5H), 7.38 (d, J=8.3 Hz, 1H), 7.21 (d, J=8.5Hz, 2H), 5.48-5.28 (m, 2H), 4.39-4.15 (m, 2H), 3.74 (s, 2H), 3.22-3.13(m, 2H), 3.12-3.05 (m, 2H), 2.88-2.73 (m, 2H), 2.70-2.56 (m, 1H),1.85-1.80 (m, 2H), 1.70-1.61 (m, 2H), 1.49 (s, 9H). LCMS-A: rt 6.646min; m/z 652 [M+H]⁺.

(g)2-(2-(2-(2-((4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-4-(trifluoromethyl)phenyl)acetamide(17)

TFA (0.1 mL) was added to a solution of tert-butyl4-(4-((4-(2-(2-amino-2-oxoethyl)-5-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A62) (0.170 g, 0.261 mmol) in DCM (4 mL) and the resulting mixturestirred for 24 hours at room temperature. The volatiles were evaporatedunder reduced pressure then the residue adsorbed onto silica gel andpurified by column chromatography (SiO₂, 1-50% MeOH in DCM). Thevolatiles were removed in vacuo and the residue dissolved in dry MeOH (5mL). Formaldehyde (37 wt. % in H₂O; 0.030 mL, 0.36 mmol) was added andthe resulting mixture was stirred for 30 minutes at room temperature.Sodium triacetoxyborohydride (0.077 g, 0.362 mmol) was added undernitrogen and the resulting mixture stirred at room temperature for 2hours. The volatiles were evaporated under reduced pressure then theresidue dissolved in EtOAc and washed with 10% NaHCO₃ (20 mL). Theorganics were dried (MgSO₄) and the volatiles removed under reducedpressure. The residue was adsorbed onto silica gel, then purified bysilica gel column chromatography (Biotage Isolera, SiO₂ cartridge,50-100% MeOH in EtOAc then 10% NH₃ in EtOH). Further purification bysemi preparative HPLC was required to give the title compound 17 as apale cream solid (0.011 g, 26%); ¹H NMR (400 MHz, d₄-MeOH) δ 8.55 (s,1H), 7.67-7.60 (m, 2H), 7.50-7.40 (m, 3H), 7.28-7.19 (m, 2H), 3.74 (s,2H), 3.54-3.40 (m, 2H), 3.31-3.25 (m, 2H), 3.14-3.12 (m, 2H), 2.95 (t,J=11.5 Hz, 2H), 2.80 (m, 4H), 2.08 (d, J=13.8 Hz, 2H), 1.97-1.92 (m,2H). LCMS-B: rt 4.52 min; m/z 566 [M+H]⁺.

Example 18 Synthesis of2-(2-(2-(2-(4-(1-aminoethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(18)

(a) tert-Butyl1-(4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)ethylcarbamate(A63)

ZnCl₂ (1.0 M in Et₂O; 3.27 mL, 3.27 mmol) was added to a stirredsolution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (620 mg, 2.86mmol) in a 1:1 t-BuOH:DCE mixture (120 mL) at room temperature. Afterstirring for 20 minutes tert-butyl 1-(4-aminophenyl)ethylcarbamate(0.643 g, 2.72 mmol) (prepared according to Bioorganic and MedicinalChemistry Letters, 14(7), 1751-1755; 2004) followed by Et₃N (455 μL,3.27 mmol) was added and the resulting mixture stirred at roomtemperature overnight. The volatiles were evaporated to dryness and theresulting residue purified by silica gel column chromatography(CombiFlash Rf, SiO₂ cartridge, 0-10% EtOAc in cyclohexane) to give thetitle compound A63 (480 mg, 42%); ¹H NMR (300 MHz, CDCl₃) δ 8.57 (s,1H), 7.56 (m, 1H), 7.56 (d, J=8.61 Hz, 2H), 7.33 (d, J=8.61 Hz, 2H),4.81 (m, 2H), 1.46 (m, 12H). LCMS-B: rt 8.47 min; m/z 417 [M+H]⁺.

(b) Methyl2-(2-((2-(4-(1-(tert-butoxycarbonylamino)ethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetate(A64)

A suspension of tert-butyl1-(4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)ethylcarbamate(A63) (487 mg, 1.17 mmol), Et₃N (760 μL), methyl2-(2-ethynylphenyl)acetate (K1) (244 mg, 1.40 mmol), PdCl₂(PPh₃)₂ (41mg, 0.058 mmol), CuI (22.0 mg, 0.117 mmol) and PPh₃ (36.0 mg, 0.117mmol) in DMF (4.6 mL) was heated under microwave irradiation at 120° C.for 15 minutes. The volatiles were evaporated in vacuo and the residuepurified by silica gel column chromatography (CombiFlash Rf, SiO₂cartridge, 0-25% EtOAc in cyclohexane) to give the title compound A64 asa yellow solid (400 mg, 62%); ¹H NMR (300 MHz, CDCl₃) δ 8.66 (s, 1H),7.70 (dd, J=7.83, 1.17 Hz, 1H), 7.61 (d, J=8.61 Hz, 2H), 7.43 (m, 3H),7.34 (d, J=8.40 Hz, 2H), 4.78 (m, 2H), 3.98 (s, 2H), 3.73 (s, 3H), 1.61(s, ¹H, peak obscured),1.46 (m, 12H). LCMS-B: rt 8.90 min; m/z 555[M+H]⁺.

(c) Methyl2-(2-(2-(2-(4-(1-(tert-butoxycarbonylamino)ethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate(A65)

A suspension of methyl2-(2-((2-(4-(1-(tert-butoxycarbonylamino)ethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetate(A64) (353 mg, 0.637 mmol) and Pd/C (10%; 250 mg) in EtOAc (13 mL) wasstirred under a hydrogen atmosphere at room temperature overnight. Theresulting mixture was filtered through a pad of Celite then the filtrateevaporated under reduced pressure to give the title compound A65 as anoff white solid (320 mg, 90%); ¹H NMR (300 MHz, CDCl₃) δ 8.56 (s, 1H),7.61 (d, J=8.64 Hz, 2H), 7.52 (s, 1H), 7.28 (m, 5H), 4.81 (m. s, 2H),3.77 (s, 2H), 3.70 (s, 3H), 3.13 (m, 4H), 1.66 (m, ¹H, peak obscured),1.48 (d, J=6.54 Hz, 3H), 1.45 (s, 9H). LCMS-B: rt 9.07 min; m/z 559.5[M+H]⁺.

(d)2-(2-(2-(2-(4-(1-(tert-Butoxycarbonylamino)ethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)aceticacid (A66)

LiOH (69.0 mg, 2.86 mmol) was added to a solution of methyl2-(2-(2-(2-(4-(1-(tert-butoxycarbonylamino)ethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate(A65) (320 mg, 0.573 mmol) in THF (7.5 mL) and water (2.5 mL) and theresulting mixture stirred at room temperature overnight. The resultingmixture was evaporated in vacuo then the residue was partitioned betweenEtOAc (15 mL) and 1 M aqueous HCl. The phases were separated and theaqueous phase was extracted with EtOAc. The combined organic phases werewashed with brine, dried with Na₂SO₄ and concentrated to give the titlecompound A66 (310 mg, 99%); LCMS-B: rt 8.30 min; m/z 545.4 [M+H]⁺.

(e)2-(2-(2-(2-(4-(1-(tert-Butoxycarbonylamino)ethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)aceticacid (A67)

HOBt (119 mg, 0.881 mmol), EDCl.HCl (169 mg, 0.881 mmol) and DIPEA (512μL, 2.94 mmol) were added to a stirred solution of2-(2-(2-(2-(4-(1-(tert-butoxycarbonylamino)ethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)aceticacid (A66) (320 mg, 0.588 mmol) in dry THF (7.0 mL) and dry DMF (1.5 mL)under an atmosphere of nitrogen. After 10 minutes ammonium carbonate(282 mg, 2.94 mmol) was added in one portion and the resulting mixturewas stirred at 40° C. overnight. The volatiles were removed in vacuo,then the residue was partitioned between EtOAc (50 mL) and saturatedNaHCO₃ (50 mL). After separating the organic layer, the aqueous phasewas extracted with EtOAc (2×50 mL). The combined organics wereconcentrated under reduced pressure then purified by silica gel columnchromatography (CombiFlash Rf, SiO₂ cartridge, 0-60% EtOAc incyclohexane) to give the title compound A67 (307 mg, 96%); ¹H NMR (300MHz, CDCl₃) δ 8.51 (s, 1H), 7.95 (br.s, 1H), 7.56 (d, J=8.52 Hz, 2H),7.27 (m, 5H), 5.91 (m, 1H), 5.53 (br.s, 1H), 5.03 (m, 1H), 4.78 (m, 1H),3.70 (s, 2H), 3.10 (m, 4H), 2.00 (br.s, 1H), 1.44 (m, 12H). LCMS-B: rt7.85 min; m/z 544.4 [M+H]⁺.

(f) tert-Butyl1-(4-(4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)ethylcarbamate(18)

A solution of2-(2-(2-(2-(4-(1-(tert-butoxycarbonylamino)ethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)aceticacid (A67) (143 mg, 0.263 mmol) and TFA (806 μL, 1.20 mmol) in DCM (40mL) was stirred at room temperature overnight. The volatiles wereremoved under reduced pressure and the residue azeotroped with toluene(×3). The residue was then dissolved in MeOH and applied to an SCXcartridge which was washed with MeOH followed by ethanolic ammoniasolution (5 M). The ethanolic ammonia fractions were evaporated in vacuoto give the title compound 18 as a light yellow solid (114 mg, 98%); ¹HNMR (300 MHz, d₆-DMSO) δ 10.13 (s, 1H), 8.66 (s, 1H), 7.66 (d, J=8.61Hz, 2H), 7.44 (brs, 1H), 7.31 (d, J=8.40 Hz, 2H), 7.24 (m, 1H), 7.18 (m,3H), 6.92 (brs, 1H), 3.95 (q, J=6.48 Hz, 1H), 3.51 (s, 2H), 3.33 (peakobscured), 3.11 (m, 4H), 1.24 (d, J=6.60 Hz, 2H). LCMS-B: rt 5.28 min;m/z 444.3 [M+H]⁺.

Example 19 Synthesis of2-(2-(2-(2-((4-(((2-hydroxyethyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(19)

(a) 2-((4-Nitrobenzyl)amino)ethanol (A68)

A solution of ethanolamine (10.05 mL, 166.6 mmol), DIPEA (5.08 mL, 29.2mmol) and 4-nitrobenzyl bromide (6.00 g, 27.8 mmol) in DCM (50 mL) wasstirred at room temperature for 4 hours. The volatiles were removed invacuo and the resulting residue partitioned between water and EtOAc. Theaqueous phase was separated and extracted with EtOAc (3×30 mL). Thecombined organic fractions were washed with brine, dried (Na₂SO₄),filtered and concentrated in vacuo to give the title compound A68 as alight yellow solid (3.34 g, 61%); ¹H NMR (300 MHz, d₆-DMSO) δ 8.18 (d,J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 4.49 (t, J=5.4 Hz, 1H), 3.84 (s,2H), 3.47 (q, J=5.6 Hz, 2H), 2.56 (t, J=5.8 Hz, 2H), 2.28 (s, 1H).

(b) tert-Butyl (2-hydroxyethyl)(4-nitrobenzyl)carbamate (A69)

A solution of di-tert-butyl dicarbonate (1.79 g, 8.23 mmol) in DCM (17mL) was added slowly to a solution of 2-((4-nitrobenzyl)amino)ethanol(A68) (1.60 g, 8.15 mmol) and 2 M aqueous sodium hydroxide (6.11 mL,12.23 mmol) in DCM (17 mL). The resulting mixture was stirred at roomtemperature for 18 hours then diluted with water and DCM. The layersseparated and the aqueous phase was extracted with DCM (3×20 mL). Thecombined organic fractions were washed with brine, dried (Na₂SO₄),filtered and concentrated in vacuo to give the title compound A69 as aviscous colourless oil (2.40 g, 99%); ¹H NMR (300 MHz, CDCl₃) δ 8.22 (d,J=8.6 Hz, 2H), 7.42 (d, J=8.6 Hz, 2H), 4.61 (s, 2H), 3.77 (m, 2H), 3.46(s, 2H), 2.72 (t, J=5.4 Hz, 1H), 1.44 (brs, 9H).

(c) tert-Butyl 4-aminobenzyl(2-hydroxyethyl)carbamate (A70)

A suspension of tert-butyl (2-hydroxyethyl)(4-nitrobenzyl)carbamate(A69) (2.40 g, 8.09 mmol) and 10% Pd/C (0.240 g) in EtOAc (12 mL) wasstirred under a hydrogen atmosphere for 18 hours. The resulting mixturewas filtered through a pad of Celite, washing with EtOAc and thefiltrate concentrated in vacuo. The residue was purified using silicagel column chromatography (CombiFlash Rf, 40 g SiO₂ cartridge, 20-50%EtOAc in cyclohexane) to give the title compound A70 as a viscous lightyellow oil (1.99 g, 92%); ¹H NMR (300 MHz, CDCl₃) δ 7.05 (d, J=7.5 Hz,2H), 6.66 (d, J=8.0 Hz, 2H), 4.37 (s, 2H), 3.67 (m, 4H), 3.37 (s, 2H),3.10 (s, 1H), 1.50 (s, 9H).

(d) tert-Butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl(2-hydroxyethyl)carbamate(A71)

Zinc(II) chloride (1.0 M in Et₂O; 3.30 mL, 3.30 mmol) was added to asolution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.658 g, 3.03mmol) in 1:1 DCE/t-BuOH (20 mL) at 0° C. under nitrogen. After stirringfor 1 hour at 0° C., a solution of tert-butyl4-aminobenzyl(2-hydroxyethyl)carbamate (A70) (0.734 g, 2.75 mmol) in 1:1DCE/t-BuOH (20 mL) was added followed by a solution of Et₃N (0.423 mL,3.03 mmol) in 1:1 DCE/t-BuOH (5 mL) at 0° C. The resulting mixture wasvigorously stirred at 0° C. for 30 minutes, then at room temperature for20 hours. The volatiles were evaporated in vacuo and the residueadsorbed onto silica gel then purified by column chromatography(CombiFlash Rf, 80 g SiO₂ cartridge, 10-40% EtOAc in cyclohexane) togive the title compound A71 as a white solid (1.06 g, 85%); ¹H NMR (300MHz, CDCl₃) δ 8.60 (s, 1H), 7.59-7.52 (m, 3H), 7.28 (m, 2H), 4.49 (s,2H), 3.74 (s, 2H), 3.43-3.20 (m, 3H), 1.50 (s, 9H). LCMS-B: rt 7.856min; m/z 447 [M+H]⁺.

(e) Methyl2-(2-((2-((4-(((tert-butoxycarbonyl)(2-hydroxyethyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetate(A72)

A suspension of tert-butyl4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl(2-hydroxyethyl)carbamate(A71) (0.518 g, 1.15 mmol), Et₃N (0.75 mL), methyl2-(2-ethynylphenyl)acetate (K1) (0.242 g, 1.39 mmol), PdCl₂(PPh₃)₂(0.041 g, 0.058 mmol), CuI (0.022 g, 0.116 mmol) and PPh₃ (0.030 g, 0.12mmol) in DMF (4.5 mL) was heated under microwave irradiation at 120° C.for 15 minutes. The volatiles were evaporated in vacuo and the residuepurified using silica gel column chromatography (CombiFlash Rf, 40 gSiO₂ cartridge, 20-50% EtOAc in cyclohexane) to give the title compoundA72 as an orange foam (0.589 g, 86%); ¹H NMR (300 MHz, CDCl₃) δ 8.65 (s,1H), 7.70 (d, J=7.0 Hz, 1H), 7.63 (d, J=8.3 Hz, 2H), 7.48-7.28 (m, 6H),4.49 (brs, 2H), 3.97 (s, 2H), 3.72 (m, 5H), 3.47 (brs, 2H), 3.01 (brs,1H), 1.51 (s, 9H). LCMS-B: rt 8.350 min; m/z 585 [M+H]⁺.

(f) Methyl2-(2-(2-(2-((4-(((tert-butoxycarbonyl)(2-hydroxyethyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate(A73)

A suspension of methyl2-(2-((2-((4-(((tert-butoxycarbonyl)(2-hydroxyethyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetate(A72) (0.589 g, 1.00 mmol) and 10% Pd/C (0.300 g) in EtOAc (13 mL) wasstirred under a hydrogen atmosphere for 18 hours. A further portion of10% Pd/C (0.300 g) was added and the resulting mixture stirred under ahydrogen atmosphere for 20 hours. The resulting mixture was filteredthrough a pad of Celite, washing with EtOAc and the filtrateconcentrated in vacuo. The residue was purified using silica gel columnchromatography (CombiFlash Rf, 24 g SiO₂ Cartridge, 20-60% EtOAc incyclohexane) to give the title compound A73 as a light yellow gum (0.443g, 74%); ¹H NMR (300 MHz, CDCl₃) δ 8.56 (s, 1H), 7.63 (d, J=8.3 Hz, 2H),7.44 (s, 1H), 7.28-7.25 (m, 6H), 4.49 (brs, 2H), 3.77-3.70 (m, 7H), 3.42(brs, 2H), 3.15-2.95 (m, 5H), 1.51 (s, 9H). LCMS-B: rt 8.469 min; m/z589 [M+H]⁺.

(g)2-(2-(2-(2-((4-(((tert-Butoxycarbonyl)(2-hydroxyethyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)aceticacid (A74)

LiOH (143 mg, 5.98 mmol) was added to a solution of methyl2-(2-(2-(2-((4-(((tert-butoxycarbonyl)(2-hydroxyethyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate(A73) (0.440 g, 0.748 mmol) in THF (10 mL), MeOH (1 mL) and water (1 mL)and the resulting mixture stirred at room temperature for 20 hours.Additional LiOH (107 mg, 4.48 mmol) was added and the mixture heated to40° C. for 24 hours. The volatiles were removed in vacuo. The residuewas diluted with a 10% citric acid solution (20 mL) and 1 M HCl (0.5 mL)until pH 3 was obtained. The resulting precipitate was collected byfiltration and dried to give the title compound A74 as a pale yellowsolid (0.421 g, 98%); ¹H NMR (300 MHz, d₆-DMSO) δ 10.21 (s, 1H), 8.67(s, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.24-7.17 (m, 6H), 4.38 (brs, 2H), 3.64(brs, 2H), 3.47-3.03 (m, 8H), 1.42 (s, 9H). LCMS-B: rt 7.786 min; m/z575 [M+H]⁺.

(h) tert-Butyl4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl(2-hydroxyethyl)carbamate(A75)

HOBt (0.119 g, 0.879 mmol) and EDCl.HCl (0.169 g, 0.879 mmol) were addedto a solution of2-(2-(2-(2-((4-(((tert-butoxycarbonyl)(2-hydroxyethyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)aceticacid (A74) (0.421 g, 0.733 mmol) and Et₃N (0.408 mL, 0.297 mmol) in DMF(10 mL). After 10 minutes ammonium carbonate (1.34 g, 14.65 mmol) wasadded and the resulting mixture was stirred at 40° C. for 22 hours.Saturated aqueous saturated NaHCO₃ solution (25 mL) was added theresulting mixture extracted with EtOAc (3×15 mL). The combined organicfractions were dried (Na₂SO₄), filtered and evaporated in vacuo. Theresidue was adsorbed onto silica gel then purified using columnchromatography (CombiFlash Rf, 24 g SiO₂ cartridge, 40-100% EtOAc incyclohexane) to give the title compound A75 as a white solid (0.301 g,76%); ¹H NMR (300 MHz, CDCl₃) δ 8.56 (s, 1H), 7.61-7.58 (m, 3H),7.30-7.26 (m, 6H), 5.48 (brs, 2H), 4.49 (brs, 2H), 3.74 (brs, 4H), 3.42(brs, 2H), 3.15-3.12 (m, 4H), 1.50 (s, 9H). LCMS-B: rt 7.344 min; m/z574 [M+H]⁺.

(i)2-(2-(2-(2-((4-(((2-Hydroxyethyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(19)

A solution of tert-butyl4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl(2-hydroxyethyl)carbamate(A75) (0.301 g, 0.525 mmol) and trifluoroacetic acid (1.0 mL) in DCM (10mL) was stirred at room temperature for 22 hours. The volatiles wereremoved in vacuo and 2 M aqueous sodium hydroxide solution (20 mL) addedto the residue. The resulting suspension was sonicated for severalminutes then filtered, washing the filter cake with water. Semipreparative HPLC of the filter cake gave the title compound 19 as awhite solid (58 mg, 23%); ¹H NMR (300 MHz, d₄-MeOH) δ 8.61 (s, 1H), 8.53(s, 1H), 7.83 (d, J=8.5 Hz, 2H), 7.46 (d, J=8.6 Hz, 2H), 7.29-7.19 (m,4H), 4.19 (s, 2H), 3.82 (t, J=5.2 Hz, 2H), 3.68 (s, 2H), 3.22-3.10 (m,6H). LCMS-B: rt 5.313 min; m/z 474 [M+H]⁺.

Example 20 Synthesis of2-(2-(2-(2-((4-(azetidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(20)

(a) tert-Butyl 3-(4-nitrophenyl)azetidine-1-carboxylate (A76)

DCE (0.146 mL, 1.69 mmol) was added to a vigorously stirred suspensionof zinc dust (0.901 g, 13.8 mmol) in THF (3.5 mL) under nitrogen. Theresulting suspension was heated at 80° C. for 10 minutes then cooled toroom temperature. Trimethylsilyl chloride (0.202 mL, 1.59 mmol) in THF(1.75 mL) was added and the mixture was stirred at room temperature for4 minutes. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (3.00g, 10.6 mmol) in THF (3.5 mL) was added dropwise over 15 minutes and theresulting mixture stirred at room temperature for 2 hours. Pd₂(dba)₃(0.155 g, 0.170 mmol) and tri-2-furylphosphine (0.143 g, 0.615 mmol)were added followed by 1-iodo-4-nitrobenzene (2.90 g, 11.7 mmol) in THF(18 mL). The resulting mixture was then heated at 55° C. for 3 hoursthen quenched with an aqueous saturated sodium chloride solution (15mL). After filtration through a pad of Celite, the layers were separatedand the aqueous phase extracted with DCM (2×15 mL). The combined organicfractions were dried (MgSO₄), filtered and evaporated in vacuo. Theresidue was purified using silica gel column chromatography (CombiFlashRf, 40 g SiO₂ cartridge, 10-40% EtOAc in cyclohexane) to give the titlecompound A76 as an orange oil (2.14 g, 72%); ¹H NMR (300 MHz, CDCl₃) δ8.24 (dd, J=6.8, 1.9 Hz, 2H), 7.51 (d, J=8.6 Hz, 2H), 4.41 (t, J=8.7 Hz,2H), 3.98 (dd, J=8.5, 5.7 Hz, 2H), 3.89-3.81 (s, 1H), 1.49 (s, 9H).

(b) tert-Butyl 3-(4-aminophenyl)azetidine-1-carboxylate (A77)

A suspension of tert-butyl 3-(4-nitrophenyl)azetidine-1-carboxylate(A76) (2.14 g, 7.68 mmol) and 10% Pd/C (0.320 g) in EtOAc (16 mL) wasstirred under a hydrogen atmosphere for 18 hours. Additional 10% Pd/C(1.00 g) was added and the mixture stirred under a hydrogen atmospherefor a further 20 hours. The resulting mixture was filtered through a padof Celite, washing with EtOAc and the filtrate concentrated in vacuo togive the title compound A77 as a light yellow/cream solid (1.80 g, 94%);¹H NMR (300 MHz, CDCl₃) δ 7.12 (d, J=8.3 Hz, 2H), 6.69 (dd, J=6.5, 1.9Hz, 2H), 4.29 (t, J=8.7 Hz, 2H), 3.93 (dd, J=8.4, 6.1 Hz, 2H), 3.69-3.61(s, 2H), 1.55-1.68 (m, 1H), 1.48 (s, 9H). LCMS-B: rt 4.964 min; m/z 249[M+H]⁺.

(c) tert-Butyl3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate(A78)

Zinc(II) chloride (1.0 M in Et₂O; 4.83 mL, 4.83 mmol) was added to asolution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.769 g, 3.54mmol) in DCE/t-BuOH (64 mL) at room temperature under nitrogen. Afterstirring for 10 minutes, tert-butyl3-(4-aminophenyl)azetidine-1-carboxylate (A77) (0.800 g, 3.22 mmol) wasadded followed by Et₃N (1.08 mL, 7.73 mmol). The resulting mixture wasstirred at room temperature for 20 hours then the volatiles removed invacuo. Water was added to the residue and the resulting suspensionsonicated for 2 minutes. The suspension was filtered and the filter cakedried then adsorbed onto silica gel and purified using columnchromatography (CombiFlash Rf, 40 g SiO₂ cartridge, 10-40% EtOAc incyclohexane) to give a white solid. The solid was suspended in MeOH (7mL) and the resulting suspension sonicated for 30 seconds. Thesuspension was filtered and the filter cake washed with MeOH (3 mL),then dried to give the title compound A78 as a white solid (0.777 g,56%); ¹H NMR (300 MHz, d₆-DMSO) δ 10.6 (s, 1H), 8.79 (s, 1H), 7.66 (d,J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 4.23 (t, J=7.6 Hz, 2H), 3.85-3.74(m, 3H), 1.40 (s, 9H). LCMS-B: rt 8.810 min; m/z 429 [M+H]⁺.

(d) tert-Butyl3-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate(A79)

A suspension of tert-butyl3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate(A78) (500 mg, 1.16 mmol), methyl 2-(2-ethynylphenyl)acetate (K1) (244mg, 1.39 mmol), Et₃N (0.60 mL), PdCl₂(PPh₃)₂ (0.041 g, 0.058 mmol), CuI(0.022 g, 0.117 mmol) and PPh₃ (0.031 g, 0.117 mmol) in DMF (4 mL) wereheated under microwave irradiation at 120° C. for 15 minutes. Theresulting mixture was adsorbed onto silica gel and purified using columnchromatography (CombiFlash Rf, 40 g SiO₂ cartridge, 0-30% EtOAc incyclohexane) to give the title compound A79 as a yellow foam (0.570 g,86%); ¹H NMR (300 MHz, d₆-DMSO) δ 8.65 (s, 1H), 7.70 (d, J=7.7 Hz, 1H),7.64 (d, J=8.5 Hz, 2H), 7.48-7.33 (m, 6H), 4.35 (t, J=8.6 Hz, 2H),4.01-3.96 (m, 4H), 3.75-3.72 (m, 4H), 1.49 (s, 9H). LCMS-B: rt 9.160min; m/z 567 [M+H]⁺.

(e) tert-Butyl3-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate(A80)

A suspension of tert-butyl3-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate(A79) (570 mg, 1.00 mmol) and 10% Pd/C (0.600 g) in EtOAc (13 mL) wasstirred under a hydrogen atmosphere for 18 hours. The resulting mixturewas filtered through a pad of Celite, washing with EtOAc and thefiltrate concentrated in vacuo to give the title compound A80 as a lightyellow foam (521 mg, 90%); ¹H NMR (300 MHz, d₆-DMSO) δ 8.56 (s, 1H),7.64 (d, J=8.5 Hz, 2H), 7.57 (s, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.28-7.25(m, 4H), 4.35 (t, J=8.7 Hz, 2H), 3.99 (dd, J=8.4, 6.7 Hz, 2H), 3.77 (m,3H), 3.70 (brs, 3H), 3.13 (m, 4H), 1.44 (s, 9H). LCMS-B: rt 9.374 min;m/z 571 [M+H]⁺.

(f)2-(2-(2-(2-((4-(1-(tert-Butoxycarbonyl)azetidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)aceticacid (A81)

LiOH.H₂O (0.219 g, 9.131 mmol) was added to a solution of tert-butyl3-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate(A80) (0.521 g, 0.913 mmol) in THF (10 mL), MeOH (1 mL) and water (1 mL)and the resulting mixture stirred at 40° C. for 20 hours. AdditionalLiOH.H₂O (0.087 g, 3.65 mmol) was added and the mixture heated at 40° C.for a further 24 hours. The volatiles were removed in vacuo and theresidue was diluted with 10% citric acid solution (20 mL). Aqueous 1 MHCl (ca 0.5 mL) was then added until a pH of 3 was obtained. EtOAc wasadded, the layers separated and the aqueous phase extracted with EtOAc(3×20 mL). The combined organics were washed with brine, dried (MgSO₄),filtered and evaporated in vacuo to give the title compound A81 as aviscous yellow oil (0.500 g, 98%); ¹H NMR (300 MHz, d₆-DMSO) δ 9.26(brs, 1H), 8.52 (s, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.32-7.24 (m, 6H), 4.31(t, J=8.7 Hz, 2H), 3.97-3.68 (m, 5H), 3.08 (m, 4H), 1.48 (s, 9H).LCMS-B: rt 8.649 min; m/z 557 [M+H]⁺.

(g) tert-Butyl3-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate(A82)

HOBt (146 mg, 1.07 mmol) and EDCl.HCl (207 mg, 1.07 mmol) were added toa solution of2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)azetidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)aceticacid (A81) (0.500 g, 0.898 mmol) and Et₃N (455 μL, 4.49 mmol) in DMF (13mL). After 10 minutes ammonium carbonate (1.65 g, 18.0 mmol) was addedand the resulting mixture was stirred at 40° C. for 22 hours. AdditionalHOBt (0.072 g, 0.539 mmol), EDCl.HCl (0.103 g, 0.539 mmol) and ammoniumcarbonate (0.413 g, 4.49 mmol) were added and the mixture stirred at 45°C. for 24 hours. The volatiles were removed in vacuo and water (25 mL)added to the residue resulting in the formation of a precipitate. Theresulting suspension was sonicated for several minutes, filtered and thefilter cake dried to give a solid which was adsorbed onto silica gel andpurified by column chromatography (CombiFlash Rf, 40 g SiO₂ cartridge,25-70% EtOAc in cyclohexane) to give the title compound A82 as a whitesolid (346 mg, 69%); ¹H NMR (300 MHz, d₆-DMSO) δ 10.21 (s, 1H), 8.68 (s,1H), 7.74 (d, J=8.6 Hz, 2H), 7.42 (s, 1H), 7.30 (d, J=8.6 Hz, 2H),7.24-7.16 (m, 4H), 6.91 (s, 1H), 4.23 (t, J=8.0 Hz, 2H), 3.85-3.71 (m,3H), 3.50 (s, 2H), 3.12-3.04 (m, 4H), 1.40 (s, 9H). LCMS-B: rt 8.187min; m/z 556 [M+H]⁺.

(h)2-(2-(2-(2-((4-(azetidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(20)

A solution of tert-butyl3-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate(A82) (0.346 g, 0.623 mmol) and trifluoroacetic acid (1 mL) in DCM (10mL) was stirred at room temperature for 22 hours. The volatiles wereremoved in vacuo and 2 M aqueous NaOH (15 mL) was added to the residue.Water (20 mL) was added and the resulting suspension sonicated for 2minutes, filtered and the filter cake washed with water and dried togive the title compound 20 as a white solid (0.283 g, 99%); ¹H NMR (300MHz, d₆-DMSO) δ 10.26 (s, 1H), 8.69 (s, 1H), 7.78 (d, J=8.6 Hz, 2H),7.43 (s, 1H), 7.36 (d, J=8.6 Hz, 2H), 7.25-7.15 (m, 4H), 6.92 (s, 1H),4.21 (brs, 2H), 4.06-3.99 (m, 3H), 3.50 (s, 2H), 3.12-3.05 (m, 5H).LCMS-B: rt 5.442 min; m/z 456 [M+H]⁺.

Example 21 Synthesis of2-(4-methyl-2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(21)

(a) 1-(2-Bromo-4-methylphenyl)-2-diazoethanone (A83)

Oxalyl chloride (0.891 mL, 10.2 mmol) was slowly added to a solution of2-bromo-4-methylbenzoic acid (813 mg, 3.78 mmol) and DMF (0.16 mL) inTHF (35 mL) under nitrogen. The resulting mixture was stirred at roomtemperature for 30 minutes, then the volatiles were removed in vacuo andthe residue azeotroped with toluene (2×20 mL). The resulting residue wastaken up in anhydrous acetonitrile (40 mL) and chilled to 0° C. under anitrogen atmosphere. A solution of TMS-diazomethane (2.0 M in Et₂O; 4.35mL, 8.70 mmol) was rapidly added and the resulting mixture was stirredat room temperature for 1 hour. EtOAc (30 mL) and saturated aqueousNaHCO₃ (20 mL) were added and the layers separated. The aqueous layerwas extracted with EtOAc (2×30 mL), then the combined organic extractswere washed with water (×2), brine, dried (MgSO₄), filtered andevaporated in vacuo. The residue was adsorbed onto silica gel andpurified by column chromatography (Biotage Isolera, 25 g SiO₂ cartridge,10-20% EtOAc in petroleum benzine 40-60° C.) to give the title compoundA83 as a yellow oil (667 mg, 74%); ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d,J=0.6 Hz, 1H), 7.36 (d, J=7.5 Hz, 1H), 7.15 (dd, J=7.8, 0.7 Hz, 1H),5.73 (s, 1H), 2.35 (s, 3H).

(b) Methyl 2-(2-bromo-4-methylphenyl)acetate (A84)

To a solution of 1-(2-bromo-4-methylphenyl)-2-diazoethanone (A83) (667mg, 2.79 mmol) in THF (4.3 mL) and MeOH (4.3 mL) was added a solution ofsilver benzoate (96 mg, 0.42 mmol) in Et₃N (1.13 mL, 11.2 mmol). Theresulting mixture was stirred for 2 hours at room temperature thenpassed through a plug of silica gel eluting with 50% EtOAc in petroleumbenzine 40-60° C. The eluent was evaporated in vacuo and the residue wasadsorbed onto silica gel and separated using silica gel columnchromatography (Biotage Isolera, 25 g SiO₂ cartridge, 0-50% EtOAc inpetroleum benzine 40-60° C.) to give the title compound A84 as a clearoil (678 mg, >99%); ¹H NMR (400 MHz, CDCl₃) δ 7.39 (d, J=0.7 Hz, 1H),7.16 (d, J=7.8 Hz, 1H), 7.07 (dd, J=7.7, 1.0 Hz, 1H), 3.76 (s, 2H), 3.70(s, 3H), 2.30 (s, 3H). LCMS-A: rt 6.070 min.

(c) Methyl 2-(4-methyl-2-((triethylsilyl)ethynyl)phenyl)acetate (A85)

A solution of triethylsilyl acetylene (0.27 mL, 1.5 mmol) in degassedDMF (4 mL) and Et₃N (2.0 mL, 15 mmol) was added to a mixture of methyl2-(2-bromo-4-methylphenyl)acetate (A84) (0.30 g, 1.2 mmol), PdCl₂(PPh₃)₂(0.043 g, 0.062 mmol), CuI (0.012 g, 0.062 mmol) and t-Bu₃PH.BF₄ (0.018g, 0.062 mmol) in degassed DMF (10 mL). The resulting mixture was heatedat 70° C. for 17 hours then diluted with EtOAc and passed through a plugof Celite, washing with EtOAc (150 mL). The filtrate was concentratedunder reduced pressure and adsorbed onto silica gel and purified bycolumn chromatography (Biotage Isolera, 40 g SiO₂ cartridge, 0-15% EtOAcin petroleum spirits) to yield the title compound A85 as a yellow oil(0.326 g, 72% purity contaminated with starting material); ¹H NMR (400MHz, CDCl₃) δ 7.32 (s, 1H), 7.15 (d, J=7.8 Hz, 1H), 7.12-7.08 (m, 1H),3.82 (s, 2H), 3.68 (s, 3H), 2.31 (s, 3H), 1.05 (t, J=7.9 Hz, 9H),0.72-0.64 (m, 6H).

(d) Methyl 2-(2-ethynyl-4-methylphenyl)acetate (A86)

TBAF (1.0 M in THF; 1.16 mL, 1.16 mmol) was added to a solution ofmethyl 2-(4-methyl-2-((triethylsilyl)ethynyl)phenyl)acetate (A85) (0.326g, 72% purity) in DCM (10 mL) at 0° C. and the resulting mixture stirredat room temperature for 5 minutes. Aqueous 10% NaHCO₃ was added and thelayers separated. The organic layer was dried (MgSO₄) and the volatilesremoved in vacuo to give a yellow oil which was adsorbed onto silica andpurified by silica gel column chromatography (Biotage Isolera, 25 g SiO₂cartridge, 0-10% EtOAc in petroleum benzine 40-60° C.) to give the titlecompound A86 (0.196 g, 71% pure: contaminated with methyl2-(2-bromo-4-methylphenyl)acetate); ¹H NMR (400 MHz, CDCl₃) δ 7.33 (s,1H), 7.19-7.12 (m, 2H), 3.82 (s, 2H), 3.70 (s, 3H), 3.25 (s, 1H), 2.31(s, 3H). LCMS-A: rt 5.900; m/z 189.2 [M+H]⁺.

(e) tert-Butyl4-(4-((4-((2-(2-methoxy-2-oxoethyl)-5-methylphenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A87)

A solution of methyl 2-(2-ethynyl-4-methylphenyl)acetate (A86) (0.196 g,71% pure) in DMF (3 mL) and Et₃N (0.309 mL, 2.22 mmol) was added to amixture of tert-butyl4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(K5) (0.371 g, 0.812 mmol), PdCl₂(PPh₃)₂ (0.078 g, 0.11 mmol), CuI(0.021 g, 0.11 mmol) and PPh₃ (0.019 g, 0.074 mmol) in DMF (3 mL). Theresulting mixture was heated under microwave irradiation at 120° C. for15 minutes then diluted with EtOAc and passed through a plug of Celite,washing with EtOAc (50 mL). The filtrate was concentrated in vacuo andthe residue purified by silica gel column chromatography (BiotageIsolera, 40 g cartridge, 0-35% EtOAc in petroleum benzine 40-60° C.) togive the title compound A87 as a yellow oil (133 mg, 30%); ¹H NMR (400MHz, CDCl₃) δ 8.61 (s, 1H), 7.74 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.44(s, 1H), 7.24-7.16 (m, 4H), 4.43-4.14 (m, 2H), 3.90 (s, 2H), 3.69 (s,3H), 2.80 (t, J=11.7 Hz, 2H), 2.63 (tt, J=12.0, 3.3 Hz, 1H), 2.34 (s,3H), 1.81 (d, J=12.7 Hz, 2H), 1.69-1.54 (m, 2H), 1.49 (s, 9H). LCMS-A:rt 7.057 min; m/z 609.3 [M+H]⁺.

(f) tert-Butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)-5-methylphenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A88)

A suspension of tert-butyl4-(4-((4-((2-(2-methoxy-2-oxoethyl)-5-methylphenylethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A87) (0.133 g, 0.219 mmol) and 10% Pd/C (53% water; 0.133 g) in DMF (7mL) and Et₃N (1 mL) was stirred under an atmosphere of hydrogen at roomtemperature for 16 hours. The resulting mixture was filtered through apad of Celite, washing with EtOAc (50 mL). The filtrate was evaporatedin vacuo and the residue purified by silica gel column chromatography(Biotage Isolera, 25 g SiO₂ cartridge, 0-35% EtOAc in petroleum benzine40-60° C.) to yield the title compound A88 as a clear oil (0.133 g,99%); ¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 1H), 7.57 (d, J=8.6 Hz, 2H),7.53 (s, 1H), 7.20 (d, J=8.5 Hz, 2H), 7.15 (d, J=7.7 Hz, 1H), 7.07 (s,1H), 7.02 (dd, J=7.7, 1.2 Hz, 1H), 4.40-4.15 (m, 2H), 3.71 (s, 2H), 3.67(s, 3H), 3.08 (m, 4H), 2.81 (t, J=12.1 Hz, 2H), 2.65 (tt, J=12.0, 3.4Hz, 1H), 2.32 (s, 3H), 1.83 (d, J=12.8 Hz, 2H), 1.62 (m, 2H), 1.49 (s,9H). LCMS-A: rt 7.156 min; m/z 613.4 [M+H]⁺.

(g)2-(2-(2-(2-((4-(1-(tert-Butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-4-methylphenyl)aceticacid (A89)

LiOH.H₂O (0.028 g, 0.65 mmol) was added to a solution of tert-butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)-5-methylphenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A88) (0.133 g, 0.217 mmol) in THF (7 mL), water (1.5 mL) and MeOH (1mL) and the resulting mixture stirred at room temperature for 27 hours.The volatiles were removed in vacuo and the residue was partitionedbetween EtOAc (50 mL) and saturated aqueous NaHCO₃ (50 mL). The layerswere separated and the aqueous layer was extracted with EtOAc (2×50 mL).The combined organic layers were washed with brine (50 mL), dried overMgSO₄ and the volatiles removed in vacuo to give the title compound A89as a white solid (0.124 g, 95%); ¹H NMR (400 MHz, d₄-MeOH) δ 8.49 (s,1H), 7.61 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 7.09 (d, J=7.7 Hz,1H), 7.00 (s, 1H), 6.96 (d, J=7.7 Hz, 1H), 4.18 (d, J=13.1 Hz, 2H), 3.65(s, 2H), 3.13-2.90 (m, 4H), 2.92-2.71 (m, 2H), 2.64 (tt, J=12.0, 3.1 Hz,1H), 2.26 (s, 3H), 1.78 (d, J=12.5 Hz, 2H), 1.61-1.49 (m, 2H), 1.47 (s,9H). LCMS-A: rt 6.736 min; m/z 599.3 [M+H]⁺.

(h) tert-Butyl4-(4-((4-(2-(2-amino-2-oxoethyl)-5-methylphenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A90)

HOBt (0.036 g, 0.27 mmol), EDCl.HCl (0.052 g, 0.27 mmol) and DIPEA (0.18mL, 1.0 mmol) were added to a solution of2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-4-methylphenyl)aceticacid (A89) (0.12 g, 0.21 mmol) in dry THF (6 mL) and dry DMF (1 mL)under a nitrogen atmosphere. After 10 minutes ammonium carbonate (0.10g, 1.0 mmol) was added in one portion and the resulting mixture stirredat room temperature for 20 hours. The volatiles were removed in vacuoand the residue dried under high vacuum. The resulting residue was takenup in dry THF (5 mL) and dry DMF (4 mL) under a nitrogen atmosphere andHOBt (0.036 g, 0.27 mmol), EDCl.HCl (0.052 g, 0.27 mmol) and DIPEA (0.18mL, 1.0 mmol) were added. After 10 minutes ammonium carbonate (0.10 g,1.0 mmol) was added in one portion and the resulting mixture was stirredat 25° C. for 22 hours. The volatiles were removed in vacuo and theresidue was partitioned between EtOAc (65 mL) and saturated aqueousNaHCO₃ (65 mL). The layers were separated and the aqueous layer wasextracted with EtOAc (2×50 mL). The combined organic layers were washedwith brine (50 mL),dried over MgSO₄, the volatiles removed in vacuo andthe residue absorbed onto silica gel and purified by columnchromatography (Biotage Isolera, 25 g SiO₂ cartridge, 0-100% EtOAc inpetroleum benzine 40-60° C.) to give the title compound A90 as a whitesolid (0.106 g, 86%); ¹H NMR (400 MHz, CDCl₃) δ 8.51 (s, 1H), 7.88 (s,1H), 7.54 (d, J=8.5 Hz, 2H), 7.18 (d, J=8.5 Hz, 2H), 7.13 (d, J=7.6 Hz,1H), 7.08-7.01 (m, 2H), 5.78 (s, 1H), 5.47 (s, 1H), 4.39-4.15 (m, 2H),3.66 (s, 2H), 3.04 (apparent s, 4H), 2.79 (t, J=12.2 Hz, 2H), 2.62 (tt,J=12.0, 3.3 Hz, 1H), 2.32 (s, 3H), 1.81 (d, J=12.7 Hz, 2H), 1.60 (qd,J=12.8, 4.2 Hz, 2H), 1.48 (s, 9H). LCMS-A: rt 6.63 min; m/z 598.4[M+H]⁺.

(i)2-(4-Methyl-2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(21)

TFA (0.5 mL) was added to a solution of tert-butyl4-(4-((4-(2-(2-amino-2-oxoethyl)-5-methylphenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A90) (0.106 g, 0.177 mmol) in DCM (5 mL) and the resulting mixturestirred at room temperature for 17 hours. The solvent was removed invacuo and the residue partitioned between EtOAc (20 mL) and 2 M aqueousNaOH (20 mL). The aqueous layer was extracted with EtOAc (2×10 mL) andthe combined organic layers washed with water (20 mL), brine (20 mL) anddried over MgSO₄. The volatiles were removed in vacuo to give a solidwhich was suspended in DCM and cyclohexane. The resulting suspension wasfiltered to give the title compound 21 as a white solid (0.085 g, 96%);¹H NMR (400 MHz, d₄-MeOH) δ 8.54 (s, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.22(d, J=8.5 Hz, 2H), 7.14 (d, J=7.7 Hz, 1H), 7.06-6.98 (m, 2H), 3.62 (s,2H), 3.28-3.21 (m, 2H), 3.15-3.08 (m, 2H), 3.08-3.01 (m, 2H), 2.86 (td,J=12.6, 2.6 Hz, 2H), 2.78-2.67 (m, 1H), 2.26 (s, 3H), 1.91 (d, J=12.0Hz, 2H), 1.74 (qd, J=12.9, 4.0 Hz, 2H). LCMS-A: rt 4.94 min; m/z 498.3[M+H]⁺.

Example 22 Synthesis of2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-6-(trifluoromethyl)phenyl)acetamide(22)

(a) Methyl 2-(2-bromo-6-(trifluoromethyl)phenyl)acetate (A91)

To a mixture of 2-(2-bromo-6-(trifluoromethyl)phenyl)acetic acid (0.306g, 1.08 mmol) in 4:1 toluene/MeOH (8 mL) was addedtrimethylsilyldiazomethane (2.0 M in Et₂O; 0.80 mL, 1.6 mmol). Theresulting mixture was stirred at room temperature for 20 hours beforediluting with EtOAc (40 mL) and washing with saturated aqueous NaHCO₃(3×40 mL). The organics were passed through a phase separation cartridgethen concentrated under reduced pressure to give the title compound A91(0.293 g, 91%); ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=8.3 Hz, 1H), 7.65(d, J=7.8 Hz, 1H), 7.29 (m, 1H), 4.04 (m, 2H), 3.72 (s, 3H).

(b) Methyl2-(2-((triethylsilyl)ethynyl)-6-(trifluoromethyl)phenyl)acetate (A92)

A mixture of CuI (0.005 g, 0.03 mmol), PdCl₂(PPh₃)₂ (0.009 g, 0.01mmol), PPh₃ (0.017 g, 0.065 mmol) and methyl2-(2-bromo-6-(trifluoromethyl)phenyl)acetate (A91) (0.213 g, 0.717 mmol)in DMF (2.0 mL) was degassed with nitrogen for several minutes beforethe addition of DIPEA (2.00 mL, 11.5 mmol) and (triethylsilyl)acetylene(0.50 mL, 2.8 mmol). The resulting mixture was then degassed withnitrogen before heating under microwave irradiation at 90° C. for 2×20minutes. The volatiles were evaporated under reduced pressure and theresidue purified using silica gel column chromatography (0-10% EtOAc inpetroleum benzine 40-60° C.) to give a mixture of product and startingmaterial. To this material, CuI (0.013 g, 0.068 mmol), PdCl₂(PPh₃)₂(0.013 g, 0.019 mmol), PPh₃ (0.030 g, 0.114 mmol), DMF (4.0 mL), DIPEA(2.00 mL, 11.5 mmol) and (triethylsilyl)acetylene (0.50 mL, 2.8 mmol)were added. The resulting mixture was heated at 100° C. for 30 minutesthen concentrated under reduced pressure and the residue purified usingsilica gel column chromatography (Biotage Isolera, SiO₂ cartridge, 5-10%EtOAc in petroleum benzine 40-60° C.) to give the title compound A92(0.175 g, 69%); ¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, J=7.7 Hz, 1H), 7.62(d, J=7.9 Hz, 1H), 7.35 (m, 1H), 4.09 (m, 2H), 3.68 (s, 3H), 1.03 (t,J=7.9 Hz, 9H), 0.67 (q, J=7.9 Hz, 6H).

(c) Methyl 2-(2-ethynyl-6-(trifluoromethyl)phenyl)acetate (A93)

K₂CO₃ (0.210 g, 1.52 mmol) was added to a solution of methyl2-(2-((triethylsilyl)ethynyl)-6-(trifluoromethyl)phenyl)acetate (A92)(0.175 g, 0.491 mmol) in MeOH (1 mL) and the mixture stirred for 10minutes at room temperature. The resulting mixture was diluted withwater (20 mL) and extracted with DCM (3×20 mL). The combined organicextracts were concentrated under reduced pressure and the residuedissolved in MeOH (1 mL). K₂CO₃ (0.204 g, 1.48 mmol) was added and themixture stirred at room temperature for 30 minutes. The resultingmixture was diluted with water (20 mL) and extracted with DCM (3×20 mL)then the combined organic extracts were concentrated under reducedpressure. The residue was dissolved in MeOH (2 mL) to which K₂CO₃ (0.230g, 1.66 mmol) was added and the resulting mixture stirred at roomtemperature for 30 minutes. Water (20 mL) was added and the mixtureextracted with DCM (3×20 mL). The combined organic extracts wereconcentrated under reduced pressure to give the title compound A93(0.113 g, 95%); ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J=7.7 Hz, 1H), 7.67(d, J=8.0 Hz, 1H), 7.38 (m, 1H), 4.08 (m, 2H), 3.70 (s, 3H), 3.35 (s,1H).

(d) tert-Butyl4-(4-((4-((2-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A94)

A mixture of methyl 2-(2-ethynyl-6-(trifluoromethyl)phenyl)acetate (A93)(0.113 g, 0.468 mmol), tert-butyl4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(K5) (0.222 g, 0.487 mmol), copper(I) iodide (0.005 g, 0.03 mmol),PdCl₂(PPh₃)₂ (0.021 g, 0.030 mmol) and t-Bu₃PH.BF₄ (0.011 g, 0.038 mmol)in DMF (2.0 mL) was degassed with nitrogen for several minutes beforethe addition of DIPEA (2.0 mL, 12 mmol) then further degassed withnitrogen for several minutes. The resulting mixture was heated undermicrowave irradiation 110° C. for 20 minutes and then a further 30minutes. The volatiles were evaporated under reduced pressure and theresidue purified using silica gel column chromatography (BiotageIsolera, SiO₂ cartridge, 0-30% EtOAc in petroleum benzine 40-60° C.) togive the title compound A94 (0.127 g, 41%); ¹H NMR (400 MHz, CDCl₃) δ8.63 (s, 1H), 7.88 (d, J=7.3 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.55 (d,J=8.5 Hz, 2H), 7.47 (t, J=7.7 Hz, 1H), 7.41 (s, 1H), 7.22 (d, J=8.5 Hz,2H), 4.25 (m, 2H), 4.17 (s, 2H), 3.69 (s, 3H), 2.81 (t, J=12.5 Hz, 2H),2.65 (m, 1H), 1.83 (d, J=12.6 Hz, 2H), 1.63 (m, 2H), 1.49 (s, 9H).LCMS-A: rt 7.12 min; m/z 661.1 [M−H]⁻.

(e) tert-Butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A95)

A suspension of tert-butyl4-(4-((4-((2-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A94) (0.127 g, 0.192 mmol) and 10% Pd/C (53% water; 0.234 g) in EtOAc(4.0 mL) and triethylamine (0.2 mL) was stirred under a hydrogenatmosphere for 20 hours. The resulting mixture was filtered throughCelite and the filtrate concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (15-30% EtOAc inpetroleum benzine 40-60° C.) to give the title compound A95 (0.106 g,83%); ¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 1H), 7.56 (m, 3H), 7.46 (d,J=7.3 Hz, 1H), 7.36 (m, 2H), 7.21 (d, J=8.5 Hz, 2H), 4.25 (m, 2H), 3.98(s, 2H), 3.68 (s, 3H), 3.11 (m, 4H), 2.81 (m, 2H), 2.64 (m, 1H), 1.83(m, 2H), 1.62 (m, 2H), 1.49 (s, 9H). LCMS-A: rt 7.19 min; m/z 665.1[M−H]⁻.

(f)2-(2-(2-(2-((4-(1-(tert-Butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-6-(trifluoromethyl)phenyl)aceticacid (A96)

LiOH (31 mg, 1.3 mmol) was added to a solution of tert-butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A95) (0.106 g, 0.159 mmol) in THF (2.0 mL), MeOH (1.0 mL) and water(1.0 mL) and the resulting mixture was stirred at room temperature for16 hours. Water (20 mL) was added and the mixture extracted with EtOAc(2×20 mL). The combined organic extracts were concentrated under reducedpressure and the residue taken up in THF (2.0 mL), MeOH (1.0 mL) andwater (1.0 mL). LiOH (0.103 g, 4.30 mmol) was added and the resultingmixture stirred for 136 hours at room temperature. The mixture wasdiluted with water (30 mL) then extracted with EtOAc (3×30 mL). Thecombined organic extracts were passed through a phase separationcartridge then concentrated under reduced pressure to give the titlecompound A96 (0.104 g, 99%); ¹H NMR (400 MHz, d₆-DMSO) δ 10.27 (bs, 1H),8.65 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.45 (d, J=7.7 Hz, 1H), 7.38 (d,J=7.6 Hz, 1H), 7.25 (dd, J=7.6, 7.6 Hz, 1H), 7.19 (d, J=8.6 Hz, 2H),4.06 (m, 2H), 3.48 (s, 2H), 3.14 (m, 2H), 3.05 (m, 2H), 2.80 (m, 2H),2.61 (m, 1H), 1.74 (m, 2H), 1.48 (m, 2H), 1.42 (s, 9H). LCMS-A: rt 6.78min; m/z 653.3 [M+H]⁺.

(g) tert-Butyl4-(4-((4-(2-(2-amino-2-oxoethyl)-3-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A97)

DIPEA (0.16 mL, 0.92 mmol) was added to a mixture of2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-6-(trifluoromethyl)phenyl)aceticacid (A96) (0.104 g, 0.160 mmol), HOBt (0.037 g, 0.27 mmol), andEDCl.HCl (0.056 g, 0.29 mmol) in DMF (5.0 mL) under a nitrogenatmosphere. After 15 minutes ammonium carbonate (0.077 g, 0.80 mmol) wasadded and stirring continued at room temperature for 24 hours.Additional HOBt (0.072 g, 0.53 mmol), EDCl.HCl (0.056 g, 0.29 mmol) andDIPEA (0.16 mL, 0.92 mmol) were added, then and after 15 minutesammonium carbonate (0.121 g, 1.26 mmol) was also added and the resultingmixture stirred at room temperature for 16 hours. The resulting mixturewas diluted with water (20 mL) then extracted with EtOAc (3×20 mL). Thecombined organic extracts were concentrated under reduced pressure andthe residue purified using silica gel column chromatography (BiotageIsolera, SiO₂ cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) togive the title compound A97 (75 mg, 72%); ¹H NMR (400 MHz, d₆-DMSO) δ10.16 (s, 1H), 8.66 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.57 (d, J=7.9 Hz,1H), 7.51 (d, J=7.4 Hz, 1H), 7.47 (s, 1H), 7.41 (dd, J=7.7, 7.7 Hz, 1H),7.19 (d, J=8.6 Hz, 2H), 6.96 (s, 1H), 4.07 (m, 2H), 3.74 (s, 2H), 3.09(m, 4H), 2.79 (m, 2H), 2.62 (m, 1H), 1.74 (m, 2H), 1.49 (m, 2H), 1.42(s, 9H). LCMS-A: rt 6.63 min; m/z 652.3 [M+H]⁺.

(h)2-(2-(2-(2-((4-(Piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-6-(trifluoromethyl)phenyl)acetamide(22)

To a solution of tert-butyl4-(4-((4-(2-(2-amino-2-oxoethyl)-3-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A97) (0.075 g, 0.12 mmol) in DCM (5 mL) was added TFA (0.20 mL, 2.6mmol) and the resulting mixture was stirred at room temperature for 16hours. The volatiles were evaporated under reduced pressure and theresidue partitioned between water (20 mL) and EtOAc. The layers wereseparated and the aqueous layer extracted with EtOAc (2×20 mL). Thecombined organic extracts were dried using a phase separation cartridgethen the volatiles were removed under reduced pressure. The residue wastriturated with Et₂O and the resulting precipitate collected byfiltration to give the title compound 22 (56 mg, 88%); ¹H NMR (400 MHz,d₆-DMSO) δ 10.22 (s, 1H), 8.67 (s, 1H), 8.29 (brs, 1H), 7.68 (d, J=8.6Hz, 2H), 7.57 (d, J=7.9 Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.48 (s, 1H),7.41 (t, J=7.8 Hz, 1H), 7.19 (d, J=8.6 Hz, 2H), 6.94 (s, 1H), 3.73 (s,2H), 3.38 (m, 2H), 3.10 (m, 4H), 2.98 (td, J=12.8, 2.6 Hz, 2H), 2.79(tt, J=11.7, 2.7 Hz, 1H), 1.93 (d, J=15.8 Hz, 2H), 1.74 (qd, J=13.8, 4.0Hz, 2H). LCMS-A: rt 4.99 min; m/z 552.3 [M+H]⁺.

Example 23 Synthesis of2-(2-(2-(5-methoxy-2-((4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(23)

(a) Methyl2-(2-((2-chloro-5-methoxypyrimidin-4-yl)ethynyl)phenyl)acetate (A98)

A solution of methyl 2-(2-ethynylphenyl)acetate (K1) (0.35 g, 2.0 mmol)in DMF (3 mL) and Et₃N (0.70 mL, 5.0 mmol) was added to a mixture of2,4-dichloro-5-methoxypyrimidine (0.30 g, 1.7 mmol), PdCl₂(PPh₃)₂ (0.12g, 0.17 mmol), CuI (0.032 g, 0.17 mmol) and PPh₃ (0.044 g, 0.17 mmol) inDMF (3 mL). The resulting mixture was heated under microwave irradiationat 120° C. for 15 minutes, then diluted with EtOAc and passed through aplug of Celite, washing with EtOAc (50 mL). The volatiles were removedin vacuo and the residue was purified by silica gel columnchromatography (Biotage Isolera, 24 g SiO₂ cartridge, 0-25% EtOAc inhexanes) to give the title compound A98 as a pale yellow solid (0.38 g,72%); ¹H NMR (400 MHz, CDCl₃) δ 8.26 (s, 1H), 7.65 (dd, J=7.6, 1.0 Hz,1H), 7.46-7.29 (m, 3H), 4.03 (s, 3H), 3.99 (s, 2H), 3.71 (s, 3H).LCMS-A: rt 5.92 min; m/z 317.1 [M+H]⁺.

(b) tert-Butyl4-(4-((5-methoxy-4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A99)

To a solution of methyl2-(2-((2-chloro-5-methoxypyrimidin-4-yl)ethynyl)phenyl)acetate (A98)(0.10 g, 0.32 mmol) in 1,4-dioxane (6 mL) was added tert-butyl4-(4-aminophenyl)piperidine-1-carboxylate (0.087 g, 0.32 mmol), Cs₂CO₃(0.41 g, 1.3 mmol), Pd₂(dba)₃ (0.030 g, 0.032 mmol) and Xantphos (0.055g, 0.095 mmol). The resulting mixture was degassed with nitrogen for 5minutes, before heating under microwave irradiation for 30 minutes at120° C., then for 60 minutes at 120° C. EtOAc (100 mL) was added and themixture was washed with water (2×25 mL), brine (25 mL), dried (MgSO₄)and then concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (Biotage Isolera, 40 g SiO₂cartridge, 0-25% EtOAc in petroleum benzine 40-60° C.) to give the titlecompound A99 as a yellow oil (0.11 g, 64%); ¹H NMR (400 MHz, CDCl₃) δ8.18 (s, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.43-7.29(m, 3H), 7.16 (d, J=8.5 Hz, 2H), 6.98 (s, 1H), 4.38-4.17 (m, 2H), 4.02(s, 2H), 3.94 (s, 3H), 3.70 (s, 3H), 2.80 (t, J=11.9 Hz, 2H), 2.62 (tt,J=12.0, 3.3 Hz, 1H), 1.82 (d, J=13.0 Hz, 2H), 1.68-1.51 (m, peakobscured), 1.49 (s, 9H). LCMS-A: rt 6.69 min; m/z 557.3 [M+H]⁺.

(c) tert-Butyl4-(4-((5-methoxy-4-(2-(2-methoxy-2-oxoethyl)phenethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A100)

A slurry of 10% Pd/C (53% water; 0.100 g) in DMF (2 mL) was added to asolution of tert-butyl4-(4-((5-methoxy-4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A99) (0.112 g, 0.201 mmol) in DMF (8 mL) and TEA (1 mL), and theresulting mixture stirred under an atmosphere of hydrogen at roomtemperature for 16 hours. The resulting mixture was filtered through apad of Celite, washing with EtOAc (50 mL). The solvent was removed invacuo and the resultant residue purified by silica gel columnchromatography (Biotage Isolera, 25 g SiO₂ cartridge, 0-65% EtOAc inpetroleum benzine 40-60° C.) to yield the title compound A100 as a paleyellow oil (0.110 g, 98%); ¹H NMR (400 MHz, CDCl₃) δ 7.95 (s, 1H), 7.50(d, J=8.6 Hz, 2H), 7.24-7.14 (m, 4H), 7.11 (d, J=8.5 Hz, 2H), 7.02 (s,1H), 4.34-4.13 (m, 2H), 3.76 (s, 3H), 3.73 (s, 2H), 3.65 (s, 3H),3.06-2.98 (m, 2H), 2.98-2.90 (m, 2H), 2.77 (t, J=12.1 Hz, 2H), 2.58 (tt,J=11.9, 3.3 Hz, 1H), 1.78 (d, J=13.0 Hz, 2H), 1.57 (qd, J=12.9, 4.5 Hz,2H), 1.46 (s, 9H). LCMS-A: rt 6.77 min; m/z 561.4 [M+H]⁺.

(d)2-(2-(2-(2-((4-(1-(tert-Butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-methoxypyrimidin-4-yl)ethyl)phenyl)aceticacid (A101)

LiOH.H₂O (0.025 g, 0.59 mmol) was added to a solution of tert-butyl4-(4-((5-methoxy-4-(2-(2-methoxy-2-oxoethyl)phenethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A100) (0.11 g, 0.20 mmol) in THF (7 mL), water (1.5 mL) and MeOH (1 mL)and the resulting mixture stirred at room temperature for 17 hours. Thevolatiles were removed in vacuo and the residue was partitioned betweenEtOAc (50 mL) and saturated aqueous NaHCO₃ (50 mL). The layers wereseparated and the aqueous layer was extracted with EtOAc (2×50 mL). Thecombined organic layers were washed with brine (50 mL), dried over MgSO₄and the volatiles removed in vacuo to give the title compound A101 as apale yellow oil (0.099 g, 92%); ¹H NMR (400 MHz, d₄-MeOH) δ 7.98 (s,1H), 7.52 (d, J=8.5 Hz, 2H), 7.22-7.04 (m, 6H), 4.16 (d, J=13.1 Hz, 2H),3.76 (s, 3H), 3.71 (s, 2H), 2.96-2.88 (m, 4H), 2.88-2.70 (m, 2H),2.65-2.55 (m, 1H), 1.76 (d, J=12.3 Hz, 2H), 1.59-1.49 (m, 2H), 1.46 (s,9H). LCMS-A: rt 6.35 min; m/z 547.3 [M+H]⁺.

(e)2-(2-(2-(5-Methoxy-2-((4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(A102)

HOBt (0.032 g, 0.24 mmol), EDCl.HCl (0.045 g, 0.24 mmol) and DIPEA (0.16mL, 0.91 mmol) were added to a solution of2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-methoxypyrimidin-4-yl)ethyl)phenyl)aceticacid (A101) (0.099 g, 0.18 mmol) in dry THF (6 mL) and dry DMF (1 mL)under nitrogen. After 10 minutes ammonium carbonate (0.087 g, 0.91 mmol)was added in one portion and the resulting mixture was stirred at roomtemperature for 66 hours. The volatiles were removed in vacuo and theresidue partitioned between EtOAc (50 mL) and saturated aqueous NaHCO₃(50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). Thecombined organic layers were washed with brine (50 mL) and dried overMgSO₄. The solvent was removed in vacuo and the residue purified bysilica gel column chromatography (Biotage Isolera, 24 g SiO₂ cartridge,0-100% EtOAc in petroleum benzine 40-60° C. followed by 0-20% MeOH inEtOAc) to give the title compound A102 as a clear oil (0.094 g, 92%); ¹HNMR (400 MHz, d₄-MeOH) δ 8.00 (s, 1H), 7.53 (d, J=8.6 Hz, 2H), 7.22 (dd,J=7.0, 3.8 Hz, 1H), 7.20-7.13 (m, 3H), 7.10 (d, J=8.6 Hz, 2H), 4.18 (d,J=13.0 Hz, 2H), 3.78 (s, 3H), 3.65 (s, 2H), 3.10-3.00 (m, 2H), 3.00-2.92(m, peak obscured, 2H), 2.90-2.71 (m, peak obscured, 2H), 2.62 (tt,J=11.9, 3.2 Hz, 1H), 1.78 (d, J=12.2 Hz, 2H), 1.60-1.49 (m, 2H), 1.47(s, 9H). LCMS-A: rt 6.20 min; m/z 546.4 [M+H]⁺.

(f)2-(2-(2-(5-Methoxy-2-((4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(23)

TFA (0.5 mL) was added to a solution of2-(2-(2-(5-methoxy-2-((4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(A102) (0.091 g, 0.17 mmol) in DCM (5 mL), and the resulting solutionstirred at room temperature for 17 hours. The volatiles were removed invacuo and the residue partitioned between EtOAc (30 mL) and 2 M aqueousNaOH (30 mL). The aqueous layer was extracted with EtOAc (2×30 mL) thenthe combined organic layers washed with water (30 mL), brine (30 mL) anddried over MgSO₄. The volatiles were removed in vacuo to give a yellowsolid. The solid was suspended in DCM and cyclohexane and the resultingsuspension filtered to give the title compound 23 as a white solid(0.031 g, 42%); ¹H NMR (400 MHz, d₄-MeOH) δ 8.04 (s, 1H), 7.54 (d, J=8.6Hz, 2H), 7.27-7.21 (m, 1H), 7.22-7.10 (m, 5H), 3.82 (s, 3H), 3.67 (s,2H), 3.25 (m, 2H obscured by solvent), 3.11-3.03 (m, 2H), 3.03-2.95 (m,2H), 2.87 (td, J=12.6, 2.6 Hz, 2H), 2.70 (tt, J=12.0, 3.5 Hz, 1H), 1.91(d, J=12.6 Hz, 2H), 1.81-1.67 (m, 2H). LCMS-A: rt 4.58 min; m/z 446.3[M+H]⁺.

Example 24 Synthesis of2-(2-(2-(5-methyl-2-(pyridin-3-ylamino)pyrimidin-4-yl)ethyl)phenyl)acetamide(24)

A mixture of2-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide (K6)(0.050 g, 0.17 mmol), 3-aminopyridine (0.019 g, 0.21 mmol), Pd(OAc)₂(0.8 mg, 0.003 mmol), Cs₂CO₃ (0.169 g, 0.518 mmol) and Xantphos (4 mg,0.007 mmol) in 1,4-dioxane (1 mL) was heated under microwave irradiationat 150° C. for 10 minutes. Water (30 mL) was added and the resultingsuspension was sonicated for 1 minute. The precipitate was collected byfiltration then adsorbed onto silica gel and purified by silica gelcolumn chromatography (CombiFlash Rf, 12 g SiO₂ cartridge, 0-10% MeOH inDCM) to give the title compound 24 as a light pink solid (6 mg, 10%); ¹HNMR (300 MHz, d₄-MeOH) δ 8.87 (s, 1H), 8.26 (d, J=7.4 Hz, 1H), 8.16 (s,1H), 8.10 (s, 1H), 7.34 (dd, J=8.1, 4.6 Hz, 1H), 7.23-7.27 (m, 1H),7.16-7.20 (m, 3H), 3.65 (s, 2H), 3.12-3.17 (m, 2H), 2.97-3.02 (m, 2H),2.12 (s, 3H). LCMS-B: rt 4.649 min; m/z 348 [M+H]⁺.

Example 25 Synthesis of2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-5-(trifluoromethyl)phenyl)acetamide(25)

(a) Methyl 2-(2-bromo-5-(trifluoromethyl)phenyl)acetate (A103)

Concentrated aqueous H₂SO₄ (1 mL) was added to a solution of2-(2-bromo-5-(trifluoromethyl)phenyl)acetonitrile (2.00 g, 7.57 mmol) inMeOH (30 mL) and the resulting mixture heated at reflux for 14 days. Thevolatiles were removed in vacuo and the residue was taken up in EtOAc(100 mL). The resulting solution was washed with 10% aqueous NaHCO₃,dried (MgSO₄), and the volatiles removed under reduced pressure to givea clear liquid which was purified by silica gel column chromatography(Biotage Isolera, SiO₂ cartridge, 0-20% EtOAc in petroleum benzine40-60° C.) to give the title compound A103 as a clear liquid (1.67 g,74%); ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J=8.3 Hz, 1H), 7.55 (d, J=2.0Hz, 1H), 7.41 (dd, J=8.3, 2.0 Hz, 1H), 3.85 (s, 2H), 3.74 (s, 3H).LCMS-A: rt 6.223 min.

(b) Methyl2-(5-(trifluoromethyl)-2-((trimethylsilyl)-ethynyl)phenyl)acetate (A104)

A suspension of methyl 2-(2-bromo-5-(trifluoromethyl)phenyl)acetate(A103) (1.00 g, 3.36 mmol), PdCl₂(PPh₃)₂ (0.118 g, 0.168 mmol),t-Bu₃PH.BF₄ (0.049 g, 0.17 mmol), CuI (0.032 g, 0.17 mmol) andtrimethylsilylacetylene (0.951 mL, 6.73 mmol) in anhydrous degassed DMF(10 mL) and Et₃N (10 mL) was stirred at 80° C. for 16 hours. Theresulting mixture was adsorbed onto silica gel and purified by columnchromatography (Biotage Isolera, SiO₂ cartridge, 0-10% EtOAc inpetroleum benzine 40-60° C.) to give the title compound A104 as anorange liquid (0.863 g, 82%); ¹H NMR (400 MHz, CDCl₃) δ 7.57 (d, J=8.0Hz, 1H), 7.53 (d, J=0.5 Hz, 1H), 7.50-7.44 (m, 1H), 3.87 (s, 2H), 3.7s(s, 3H), 0.24 (s, 9H). LCMS: rt 6.931 min; m/z 315.1 [M+H]⁺.

(c) Methyl 2-(2-ethynyl-5-(trifluoromethyl)phenyl)acetate (A105)

TBAF (1.0 M in THF; 4.29 mL, 4.29 mmol) was added to a solution ofmethyl 2-(5-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)phenyl)acetate(A104) (0.900 g, 2.86 mmol) in THF (25 mL) at 0° C. The resultingmixture was stirred at 0° C. for 5 minutes before the addition of EtOAc(50 mL) and 10% aqueous NaHCO₃ (50 mL). The layers were separated andthe organic phase dried (MgSO₄) then the solvent was evaporated underreduced pressure. The residue was adsorbed onto silica gel and purifiedby silica gel column chromatography (Biotage Isolera, SiO₂ cartridge,0-10% EtOAc in petroleum benzine 40-60° C.) to give the title compoundA105 as a light brown coloured liquid (0.498 g, 72%); ¹H NMR (400 MHz,CDCl₃) δ 7.60 (d, J=8.1 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J=8.1 Hz, 1H),3.89 (s, 2H), 3.71 (s, 3H), 3.40 (s, 1H). LCMS-A: rt 6.094 min; m/z243.1 [M+H]⁺.

(d) tert-Butyl4-(4-((4-((2-(2-methoxy-2-oxoethyl)-4-(trifluoromethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A106)

A suspension of tert-butyl4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(K5) (0.300 g, 0.656 mmol), PdCl₂(PPh₃)₂ (0.046 g, 0.066 mmol),t-Bu₃PH.BF₄ (0.019 g, 0.066 mmol), CuI (0.013 g, 0.022 mmol) and methyl2-(2-ethynyl-5-(trifluoromethyl)phenyl)acetate (A105) (0.191 g, 0.657mmol) in dry degassed DMF (4 mL) and Et₃N (4 mL) was heated at 120° C.for 20 minutes under nitrogen. The volatiles were evaporated underreduced pressure and the residue adsorbed onto silica gel then purifiedby column chromatography (Biotage Isolera, SiO₂ cartridge, 0-50% EtOAcin petroleum benzine 40-60° C.) to give the title compound A106 as ayellow solid (0.196 g, 45%); ¹H NMR (400 MHz, CDCl₃) δ 8.64 (s, 1H),7.75 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.60-7.53 (m, 4H), 7.21 (d, J=8.5Hz, 2H), 4.25 (s, 2H), 3.99 (s, 2H), 3.72 (s, 3H), 2.80 (t, J=11.9 Hz,2H), 2.64 (m, 1H), 1.82 (d, J=12.8 Hz, 2H), 1.68-1.53 (m, 2H), 1.49 (s,9H). LCMS-A: rt 7.109 min; m/z 663.3 [M+H]⁺.

(e) tert-Butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)-4-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A107)

A suspension of 10% Pd/C (0.050 g) and tert-butyl4-(4-((4-((2-(2-methoxy-2-oxoethyl)-4-(trifluoromethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A106) (0.196 g, 0.295 mmol) in DMF (20 mL) was stirred under a hydrogenatmosphere at 50 Psi pressure for 24 hours. The resulting mixture wasfiltered through Celite, washing with MeOH (2×50 mL). The filtrate wasadsorbed onto silica gel then purified by column chromatography (BiotageIsolera, SiO₂ cartridge, 0-30% EtOAc in petroleum benzine 40-60° C.) togive the title compound A107 as a light yellow liquid (0.157 g, 80%); ¹HNMR (400 MHz, CDCl₃) δ 8.54 (s, 1H), 7.54 (d, J=8.5 Hz, 2H), 7.52-7.43(m, 3H), 7.35 (d, J=7.8 Hz, 1H), 7.20 (d, J=8.5 Hz, 2H), 4.25 (brs, 2H),3.79 (s, 2H), 3.70 (s, 3H), 3.17 (m, 2H), 3.09 (m, 2H), 2.81 (t, J=11.4Hz, 2H), 2.70-2.56 (m, 1H), 1.83 (d, J=12.7 Hz, 2H), 1.72-1.55 (m, 2H),1.49 (s, 9H). LCMS-A: rt 7.199 min; m/z 667.3 [M+H]⁺.

(f)2-(2-(2-(2-((4-(1-(tert-Butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-5-(trifluoromethyl)phenyl)aceticacid (A108)

tert-Butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)-4-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A107) (0.157 g, 0.236 mmol) and LiOH.H₂O (0.080 g, 0.711 mmol) weresuspended in MeOH (2 mL), water (2 mL) and THF (2 mL) and the resultingmixture stirred for 16 hours at room temperature. The volatiles wereevaporated under reduced pressure to give the title compound A108;LCMS-A: rt 6.828 min; m/z 653.3 [M+H]⁺.

(g) tert-Butyl4-(4-((4-(2-(2-amino-2-oxoethyl)-4-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A109)

HOBt (0.042 g, 0.31 mmol), EDCl.HCl (0.049 g, 0.31 mmol) and DIPEA(0.204 mL, 1.20 mmol) were added to a solution of2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-5-(trifluoromethyl)phenyl)aceticacid (A108) (0.157 g, 0.240 mmol) in dry DMF (5 mL) and dry THF (5 mL).Ammonium carbonate (113 mg, 1.20 mmol) was then added and the resultingmixture was stirred at room temperature for 3 days. The mixture wasdiluted with EtOAc and washed with 10% aqueous NaHCO₃. The organic layerwas dried (MgSO₄) and the volatiles removed under reduced pressure. Theresidue was adsorbed onto silica gel and purified by silica gel columnchromatography (SiO₂, 0-100% EtOAc in petroleum benzine 40-60° C.) togive the title compound A109 as a colourless solid (0.121 g, 77%); ¹HNMR (400 MHz, d₄-MeOH) δ 8.56 (s, 1H), 7.60 (m, 3H), 7.55-7.48 (m, 1H),7.42 (m, 1H), 7.22 (d, J=8.5 Hz, 2H), 4.23 (d, J=13.3 Hz, 2H), 3.76 (s,2H), 3.26 (m, 2H), 3.14 (m, 2H), 2.95-2.81 (m, 2H), 2.77-2.64 (m, 1H),1.83 (m, 2H), 1.70-1.54 (m, 2H), 1.50 (s, 9H). LCMS-A: rt 6.671 min; m/z652.3 [M+H]⁺.

(h)2-(2-(2-(2-((4-(Piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-ylethyl)-5-(trifluoromethyl)phenyl)acetamide(25)

TFA (1.0 mL) was added to a solution of tert-butyl4-(4-((4-(2-(2-amino-2-oxoethyl)-4-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate(A109) (0.121 g, 0.185 mmol) in DCM (10 mL) and the resulting mixturestirred for 24 hours at room temperature. The volatiles were evaporatedunder reduced pressure and the residue was dissolved in DCM. Cyclohexanewas added and the resultant precipitate was collected by vacuumfiltration to give the title compound 25 as a cream solid (0.065 g,68%); ¹H NMR (400 MHz, d₄-MeOH) δ 8.55 (s, 1H), 7.61 (d, J=8.5 Hz, 2H),7.57 (s, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.22 (d,J=8.6 Hz, 2H), 4.73-4.49 (m, 2H), 3.74 (s, 2H), 3.28-3.21 (m, 2H),3.17-3.09 (m, 2H), 2.95 (m, 2H), 2.84-2.71 (m, 1H), 1.96 (d, J=13.6 Hz,2H), 1.79 (m, 2H). LCMS-A: rt 4.679 min; m/z 552.3 [M+H]⁺.

Example 26 Synthesis of2-(2-(2-(5-methyl-2-((4-(piperidin-4-yloxy)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(26)

(a) tert-Butyl 4-hydroxypiperidine-1-carboxylate (A110)

Sodium borohydride (0.95 g, 25 mmol) was added to a solution of1-Boc-4-piperidone (2.50 g, 12.5 mmol) in MeOH (25 mL) at 0° C. Theresulting mixture was stirred at 0° C. for 2 hours, then roomtemperature for 2 hours. The mixture was diluted with water (100 mL) andbrine (100 mL) then extracted with EtOAc (2×150 mL). The combinedorganic extracts were dried (Na₂SO₄), filtered and concentrated underreduced pressure to give the title compound A110 as a thick colorlessoil (2.47 g, 98%); ¹H NMR (400 MHz, CDCl₃) δ 3.91-3.79 (m, 3H), 3.02 (m,2H), 1.93-1.78 (m, 2H), 1.56 (d, J=4.2 Hz, 1H), 1.52-1.40 (m, 11H).

(b) tert-Butyl 4-(4-nitrophenoxy)piperidine-1-carboxylate (A111)

4-Fluoro-nitrobenzene (0.728 mL, 6.96 mmol) was added to a solution oftert-butyl 4-hydroxypiperidine-1-carboxylate (A110) (1.40 g, 6.96 mmol)and potassium tert-butoxide (1.09 g, 9.74 mmol) in anhydrous DMSO (7.5mL) and the resulting mixture was stirred for 2 hours at roomtemperature. Water and EtOAc were added to the mixture and the phaseswere separated. The aqueous phase was extracted with EtOAc, then thecombined organic extracts were washed with water, brine and dried overNa₂SO₄. The volatiles were evaporated under reduced pressure and theresidue was adsorbed onto silica gel and purified by columnchromatography (SiO₂ cartridge, 0-15% EtOAc in cyclohexane) to give thetitle compound A111 as an oil (2.20 g, 98%); ¹H NMR (300 MHz, CDCl₃); δ8.09 (d, J=9.4 Hz, 2H), 6.91 (d, J=9.3 Hz, 2H), 4.58 (m, 1H), 3.65 (m,2H), 3.33 (m, 2H), 1.92 (m, 2H), 1.72 (m, 2H), 1.41 (s, 9H). LCMS-B: rt8.22 min; m/z 323.3 [M+H]⁺.

(c) tert-Butyl 4-(4-aminophenoxy)piperidine-1-carboxylate (A112)

Pd/C (10%; 510 mg) was added to a solution of tert-butyl4-(4-nitrophenoxy)piperidine-1-carboxylate (A111) (2.21 g, 6.86 mmol) inmethanol (30 mL) and the resulting mixture was stirred under a hydrogenatmosphere overnight. The mixture was filtered through Celite and thefiltrate concentrated under reduced pressure to afford the titlecompound A112 (1.13 g, 56%); ¹H NMR (300 MHz, CDCl₃); δ 6.68 (d, J=8.8Hz, 2H), 6.52 (d, J=8.7 Hz, 2H), 4.17 (m, 1H), 3.63 (m, 4H), 3.20 (m,2H), 1.78 (m, 2H), 1.61 (m, 2H), 1.40 (s, 9H). LCMS-B: rt 5.05 min; m/z293.2 [M+H]⁺.

(d) tert-Butyl4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenoxy)piperidine-1-carboxylate(A113)

A suspension of2-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide (K6)(0.150 g, 0.518 mmol), tert-butyl4-(4-aminophenoxy)piperidine-1-carboxylate (A112) (0.182 g, 0.621 mmol),Pd(OAc)₂ (2.3 mg, 0.010 mmol), Cs₂CO₃ (0.506 g, 1.55 mmol) and Xantphos(12 mg, 0.021 mmol) in 1,4-dioxane (2 mL) was heated under microwaveirradiation at 100° C. for 45 minutes. Water (20 mL) and EtOAc (20 mL)were added and the resulting suspension sonicated for 1 minute and thenfiltered through Celite. The resulting mixture was extracted with EtOAc(×2) and the combined organic extracts were washed with brine, dried(MgSO₄), filtered and evaporated in vacuo. The residue was purifiedusing silica gel column chromatography (CombiFlash Rf, 12 g SiO₂cartridge, 0-10% MeOH in DCM) to give the title compound A113 as a lightpink colored foam (50 mg, 18%); ¹H NMR (300 MHz, d₄-MeOH) δ 8.04 (s,1H), 7.52 (d, J=8.9 Hz, 2H), 7.18-7.27 (m, 5H), 6.92 (d, J=9.0 Hz, 2H),4.47-4.52 (m, 1H), 4.10-4.13 (m, 2H), 3.67-3.77 (m, 2H), 3.65 (s, 3H),3.37 (m, 2H), 3.09-3.15 (m, 2H), 2.93-2.98 (m, 2H), 1.91-2.03 (m, 2H),1.64-1.78 (m, 2H), 1.51 (s, 9H). LCMS-B: rt 7.302 min; m/z 546 [M+H]⁺.

(e)2-(2-(2-(5-methyl-2-((4-(piperidin-4-yloxy)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(26)

TFA (0.5 mL) was added to a cooled (water/ice bath 6° C.) solution oftert-butyl4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenoxy)piperidine-1-carboxylate(A113) (0.050 g, 0.092 mmol) in DCM (2 mL) and the resulting mixture wasstirred at room temperature for 4 hours. The volatiles were removed invacuo then 2 M aqueous K₂CO₃ solution (10 mL) and water (10 mL) wereadded to the residue. The resulting suspension was sonicated for 1minute, filtered and the filter cake dried to give the title compound 26as a light pink solid (0.034 g, 83%); ¹H NMR (300 MHz, d₆-DMSO) δ 9.17(s, 1H), 8.12 (s, 1H), 7.62 (d, J=8.9 Hz, 2H), 7.43 (s, 1H), 7.12-7.27(m, 4H), 6.93 (s, 1H), 6.84 (d, J=8.9 Hz, 2H), 4.23-4.29 (m, 1H), 3.49(s, 2H), 3.30-3.34 (m, 2H), 2.83-3.05 (m, 7H), 2.05 (s, 3H), 1.86-1.90(m, 2H), 1.39-1.42 (m, 2H). LCMS-B: rt 4.717 min; m/z 446 [M+H]⁺.

Example 27 Synthesis of2-(2-(2-(2-((4-(aminomethyl)phenyl)amino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide(27)

(a) tert-Butyl4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)benzylcarbamate(A114)

A suspension of2-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide (K6)(0.150 g, 0.518 mmol), 4-(N-Boc-aminomethyl)aniline (0.145 g, 0.621mmol), Pd(OAc)₂ (2.3 mg, 0.010 mmol), Cs₂CO₃ (0.506 g, 1.55 mmol) andXantphos (12 mg, 0.021 mmol) in 1,4-dioxane (2 mL) was heated undermicrowave irradiation at 100° C. for 1.5 hours. The resulting mixturewas filtered through a plug of silica gel, washing with 10% MeOH in DCM.The volatiles were removed in vacuo and the residue was adsorbed ontosilica gel and the product purified using silica gel columnchromatography (CombiFlash Rf, 12 g SiO₂ cartridge, 0-5% MeOH in DCM) togive the title compound A114 as a white solid (0.043 g, 17%); ¹H NMR(300 MHz, d₄-MeOH) δ 8.07 (brs, 1H), 7.59 (brs, 2H), 7.19 (m, 6H), 4.19(brs, 2H), 3.64 (brs, 2H), 3.11 (brs, 2H), 2.95-2.98 (m, 2H), 2.08 (brs,3H), 1.46 (brs, 9H). LCMS-B: rt 6.636 min; m/z 476 [M+H]⁺.

(b)2-(2-(2-(2-((4-(Aminomethyl)phenyl)amino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide(27)

TFA (1 mL) was added to a solution of tert-butyl4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)benzylcarbamate(A114) (0.043 g, 0.090 mmol) in DCM (3 mL) and the resulting solutionstirred at room temperature for 4 hours. The volatiles were removed invacuo then 2 M aqueous K₂CO₃ (5 mL) and water (15 mL) were added to theresidue. The resulting suspension was sonicated for 1 minute, filteredand the filter cake dried to give the title compound 27 as a light tansolid (0.028 g, 82%); ¹H NMR (300 MHz, d₆-DMSO) δ 9.30 (s, 1H), 8.16 (s,1H), 7.70 (d, J=8.5 Hz, 2H), 7.43 (s, 1H), 7.12-7.27 (m, 6H), 6.93 (s,1H), 3.64 (s, 2H), 3.49 (s, 2H), 3.34 (brs, 2H), 3.02-3.07 (m, 2H),2.85-2.90 (m, 2H), 2.06 (s, 3H). LCMS-B: rt 4.666 min; m/z 376 [M+H]⁺.

Example 28 Synthesis of2-(2-(2-(5-methyl-2-((1-methyl-¹H-pyrazol-4-yl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(28)

(a) Methyl2-(2-((5-methyl-2-((1-methyl-¹H-pyrazol-4-yl)amino)pyrimidin-4-yl)ethynyl)phenyl)acetate(A115)

To a solution of methyl2-(2-((2-chloro-5-methylpyrimidin-4-yl)ethynyl)phenyl)acetate (K7)(0.200 g, 0.665 mmol) in 1,4-dioxane (8 mL) was added1-methyl-¹H-pyrazol-4-amine (0.065 g, 0.665 mmol), Cs₂CO₃ (0.867 g, 2.66mmol), Pd₂(dba)₃ (0.061 g, 0.067 mmol) and Xantphos (0.115 g, 0.200mmol). The resulting mixture was degassed with nitrogen for 5 minutesbefore heating under microwave irradiation for 30 minutes at 120° C. Themixture was diluted with EtOAc (100 mL), washed with water (2×25 mL),brine (25 mL), dried (Na₂SO₄) and concentrated under reduced pressure.The resulting brown oil was purified by silica gel column chromatography(Biotage Isolera, 40 g SiO₂ cartridge, 0-100% EtOAc in hexanes) to givethe title compound A115 as a yellow solid (0.128 g, 53%); ¹H NMR (400MHz, d₆-DMSO) δ 9.47 (s, 1H), 8.39 (s, 1H), 7.89 (s, 1H), 7.67 (d, J=7.4Hz, 1H) 7.51-7.44 (m, 3H), 7.43-7.37 (m, 1H), 3.98 (s, 2H), 3.81 (s,3H), 3.61 (s, 3H), 2.25 (s, 3H). LCMS-A: rt 5.856 min; m/z 362 [M+H]⁺.

(b) Methyl2-(2-(2-(5-methyl-2-((1-methyl-¹H-pyrazol-4-yl)amino)pyrimidin-4-yl)ethyl)phenyl)acetate(A116)

10% Pd/C (53% water; 0.020 g) was added to a solution of methyl2-(2-((5-methyl-2-((1-methyl-¹H-pyrazol-4-yl)amino)pyrimidin-4-ylethynyl)phenyl)acetate(A115) (0.115 g, 0.318 mmol) in DMF (5 mL) and Et₃N (0.5 mL) and theresulting suspension placed under a hydrogen atmosphere and stirred atroom temperature for 18 hours. The mixture was filtered through Celite,washing with EtOAc (250 mL). The combined filtrates were washed withwater (100 mL) then brine (100 mL) and the washing repeated 3 times. Theorganic layer was dried (Na₂SO₄), filtered and concentrated underreduced pressure and the resulting oil purified by silica gel columnchromatography (Biotage Isolera, 24 g SiO₂ cartridge, 0-100% EtOAc inhexanes) to give the title compound A116 as a yellow solid (0.097 g,83%); ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.83 (s, 1H), 7.46 (s,1H), 7.25-7.17 (m, 4H), 6.75 (s, 1H), 3.89 (s, 3H), 3.72 (s, 2H), 3.67(s, 3H), 3.09 (dd, J=9.5, 6.3 Hz, 2H), 2.91 (dd, J=9.5, 6.4 Hz, 2H),2.07 (s, 3H). LCMS-A: rt 5.160 min; m/z 366 [M+H]⁺.

(c)2-(2-(2-(5-Methyl-2-((1-methyl-¹H-pyrazol-4-yl)amino)pyrimidin-4-yl)ethyl)phenyl)aceticacid (A117)

LiOH.H₂O (0.534 g, 12.7 mmol) was added to a solution of methyl2-(2-(2-(5-methyl-2-((1-methyl-¹H-pyrazol-4-yl)amino)pyrimidin-4-yl)ethyl)phenyl)acetate(A116) (0.093 g, 0.25 mmol) in H₂O (1 mL) and THF (10 mL) and theresulting mixture heated at 40° C. for 18 hours. The volatiles wereremoved in vacuo and the residue was diluted with EtOAc (100 mL), washedwith aqueous 2 M HCl (50 mL), water (100 mL), brine (50 mL) and driedover MgSO₄. The combined aqueous layers were additionally extracted withchloroform/isopropanol (4:1, 2×50 mL). The organic extracts were thencombined, dried (Na₂SO₄), filtered and concentrated under reducedpressure to give the title compound A117 as a yellow solid (0.067 g,75%); LCMS-A: rt 4.718 min; m/z 352 [M+H]⁺.

(d)2-(2-(2-(5-methyl-2-((1-methyl-¹H-pyrazol-4-yl)-amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(28)

HOBt (0.074 g, 0.55 mmol), EDCl.HCl (0.117 g, 0.610 mmol) and DIPEA(0.16 mL, 0.94 mmol) were added to a solution of2-(2-(2-(5-methyl-2-((1-methyl-¹H-pyrazol-4-yl)amino)pyrimidin-4-yl)ethyl)phenyl)aceticacid (A117) (0.066 g, 0.19 mmol) in dry DMF (5 mL) under an atmosphereof nitrogen. After 10 minutes ammonium carbonate (0.180 g, 1.88 mmol)was added in one portion and the resulting mixture stirred for 18 hoursat room temperature. The volatiles were removed in vacuo and the residuepartitioned between EtOAc (50 mL) and aqueous saturated NaHCO₃ (50 mL).The aqueous layer was extracted with EtOAc (2×25 mL). The combinedorganic layers were washed with brine (25 mL) and dried over Na₂SO₄. Thesolvent was removed in vacuo and the residue purified by silica gelcolumn chromatography (Biotage Isolera, 24 g SiO₂ cartridge, 0-100%EtOAc in petroleum benzine 40-60° C. followed by 0-30% MeOH in EtOAc) togive the title compound 28 as a yellow solid (0.040 g, 61%); ¹H NMR (400MHz, d₆-DMSO) δ 9.18 (s, 1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.43 (s, 2H),7.28-7.10 (m, 4H), 6.93 (s, 1H), 3.78 (s, 3H), 3.49 (s, 2H), 3.07-2.98(m, 2H), 2.90-2.81 (m, 2H), 2.04 (s, 3H). LCMS-A: rt 4.464 min; m/z 351[M+H]⁺.

Example 29 Synthesis of methyl1-(4-(4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-ylamino)phenyl)cyclobutylcarbamate(29)

(a) Methyl 1-(4-nitrophenyl)cyclobutylcarbamate (A118)

A drop of DMF and oxalyl chloride (0.283 mL, 3.30 mmol) was added to astirred solution of 1-(4-nitrophenyl)cyclobutanecarboxylic acid (503 mg,2.27 mmol) in DCM (7 mL) under a nitrogen atmosphere and the resultingmixture was stirred for 25 minutes at room temperature. The volatileswere removed in vacuo and the residue was dissolved in acetone (4.50mL). A solution of sodium azide (400 mg, 5.23 mmol) in water (4.50 mL)was added with the temperature maintained below 0° C. After stirring for30 minutes, the mixture was diluted with chloroform and washed with coldwater and saturated aqueous NaCl. The organics were dried with Na₂SO₄and concentrated carefully. Toluene (10.0 mL) was added and theresulting solution was heated at 80° C. for 1 hour. MeOH (10 mL) wasadded and the resulting mixture heated at 60° C. for 1.5 hours under anitrogen atmosphere. The volatiles were evaporated under reducedpressure then the residue adsorbed on silica gel and purified usingsilica gel column chromatography (CombiFlash Rf, SiO₂ cartridge, 0-20%EtOAc in cyclohexane) to give the title compound A118 (404 mg, 71%); ¹HNMR (300 MHz, CDCl₃): δ 8.17 (d, J=9.0 Hz, 2H), 7.59 (d, J=8.9 Hz, 2H),5.74 (br s, 1H), 3.57 (s, 3H), 2.52 (m, 4H), 2.15 (m, 1H), 1.92 (m, 1H);LCMS-B: rt 6.55 min; m/z 251.3 [M+H]⁺.

(b) Methyl 1-(4-aminophenyl)cyclobutylcarbamate (A119)

A suspension of Pd/C (10%) (120 mg) and methyl1-(4-nitrophenyl)cyclobutylcarbamate (A118) (404 mg, 1.61 mmol) in MeOH(17.0 mL) was vigorously stirred overnight under a hydrogen atmosphere.The resulting mixture was filtered through Celite then the filtrateconcentrated in vacuo. The residue was purified using silica gel columnchromatography (CombiFlash Rf, SiO₂ cartridge, 0-75% EtOAc incyclohexane) to give the title compound A119 (237 mg, 67%); ¹H NMR (300MHz, CDCl₃); δ 7.21 (d, J=8.3 Hz, 2H), 6.63 (d, J=8.5 Hz, 2H), 5.57(brs, 1H), 3.66 (s, 2H), 3.58 (s, 3H), 2.48 (m, 4H), 2.02 (m, 1H), 1.80(m, 1H). LCMS-B: rt 2.35 min; m/z 221.2 [M+H]⁺.

(c) Methyl1-(4-(4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-ylamino)phenyl)cyclobutylcarbamate(29)

A suspension of2-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide (K6)(150 mg, 0.518 mmol), Pd(OAc)₂ (11.6 mg, 0.052 mmol), Xantphos (45.0 mg,0.078 mmol), Cs₂CO₃ (486 mg, 1.49 mmol) and methyl1-(4-aminophenyl)cyclobutylcarbamate (A119) (125 mg, 0.569 mmol) in1,4-dioxane (4.0 mL) was heated under microwave irradiation for 10minutes at 150° C. The resulting mixture was filtered through Celite,and washed with EtOAc. The filtrate was concentrated under reducedpressure and the residue was purified by semi preparative HPLC to givethe title compound 29 (86 mg, 35%); ¹H NMR (300 MHz, CDCl₃): δ 8.17 (brs, 1H), 7.56 (m, 2H), 7.42 (m, 2H), 7.28 (4H, obscured by solvent peak),5.65 (br s, 1H), 5.42 (br s, 1H), 5.30 (br s, 1H), 3.70 (s, 2H), 3.61(s, 3H), 3.13 (m, 2H), 2.99 (m, 2H), 2.57 (s, 3H), 2.12-1.62 (m, 6H).LCMS-B: rt 6.28 min; m/z 474.2 [M+H]⁺.

Example 30 Synthesis of2-(2-(2-(2-((1-(azetidin-3-yl)-¹H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide(30)

(a) tert-Butyl3-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)-¹H-pyrazol-1-yl)azetidine-1-carboxylate(A120)

A suspension of2-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide (K6)(0.150 g, 0.518 mmol), 4-amino-1-(1-Boc-azetidin-3-yl)-¹H-pyrazole(0.195 g, 0.777 mmol), Pd(OAc)₂ (2.3 mg, 0.010 mmol), Cs₂CO₃ (0.506 g,1.55 mmol) and Xantphos (11.9 mg, 0.021 mmol) in 1,4-dioxane (2 mL) washeated under microwave irradiation at 100° C. for 1.5 hours.4-Amino-1-(1-Boc-azetidin-3-yl)-¹H-pyrazole (65.0 mg, 0.259 mmol) wasadded and the mixture was heated for a further 1 hour at 100° C. Theresulting mixture was adsorbed onto silica gel and purified using columnchromatography (CombiFlash Rf, 12 g SiO₂ cartridge, 0-5% MeOH in DCM) togive the title compound A120 as a light pink colored foam (0.050 g,19%); ¹H NMR (300 MHz, d₄-MeOH) δ 8.06 (d, J=8.8 Hz, 2H), 7.66 (s, 1H),7.16-7.27 (m, 4H), 5.12-5.21 (m, 1H), 4.39 (t, J=8.7 Hz, 2H), 4.25-4.30(m, 2H), 3.65 (s, 2H), 3.32 (s, 1H), 3.10-3.16 (m, 2H), 2.95-3.00 (m,2H), 2.10 (s, 3H), 1.48 (s, 9H). LCMS-B: rt 6.184 min; m/z 492 [M+H]⁺.

(b)2-(2-(2-(2-((1-(Azetidin-3-yl)-¹H-pyrazol-4-yl)-amino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide(30)

TFA (1 mL) was added to a solution of tert-butyl3-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)-¹H-pyrazol-1-yl)azetidine-1-carboxylate(A120) (0.050 g, 0.102 mmol) in DCM (3 mL) and the resulting mixturestirred at room temperature for 3 hours. The volatiles were removedunder reduced pressure then 2 M aqueous K₂CO₃ (5 mL) and water (15 mL)were added to the residue. The resulting aqueous solution was extractedwith EtOAc (3×15 mL) then the combined organic extracts were dried(MgSO₄), filtered, evaporated in vacuo and adsorbed onto silica gel. Theproduct was purified using column chromatography (CombiFlash Rf, 4 gSiO₂ Cartridge, 5-50% MeOH in DCM) to give the title compound 30 as ayellow oil (0.6 mg, 1.5%); ¹H NMR (300 MHz, d₄-MeOH) δ 8.08 (d, J=2.0Hz, 2H), 7.66 (s, 1H), 7.18-7.26 (m, 4H), 5.19-5.26 (m, 1H), 4.67 (t,J=9.0 Hz, 1H), 4.54 (dd, J=9.4, 5.3 Hz, 1H), 4.56 (t, J=9.8 Hz, 1H),4.30 (dd, J=10.4, 5.5 Hz, 1H), 3.65 (s, 2H), 3.14 (t, J=2.9 Hz, 2H),2.98-3.01 (m, 2H), 1.93 (s, 3H). LCMS-B: rt 4.426 min; m/z 392 [M+H]⁺.

Example 31 Synthesis of2-(2-(2-(2-(4-(3-aminooxetan-3-yl)phenylamino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide(31)

(a) N-(3-(4-Aminophenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide(A121)

Compound prepared using the procedure described in US2011/0172203 A1(paragraphs 2413 to 2417, which are hereby incorporated by reference)

(b)2-(2-(2-(2-(4-(3-(1,1-Dimethylethylsulfinamido)oxetan-3-yl)phenylamino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide(A122)

A suspension of2-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide (K6)(200 mg, 0.690 mmol), Pd(OAc)2(16 mg, 0.069 mmol), Xantphos (59.9 mg,0.104 mmol), Cs₂CO₃ (648 mg, 1.99 mmol) andN-(3-(4-aminophenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (A121)(204 mg, 0.759 mmol) in 1,4-dioxane (1.73 mL) was heated under microwaveirradiation for 10 minutes at 150° C. under nitrogen. The resultingmixture was filtered through Celite, washing with EtOAc. The volatileswere removed in vacuo and the residue was purified by silica gel columnchromatography (CombiFlash Rf, SiO₂ cartridge, 0-30% MeOH in DCM) togive the title compound A122 (102 mg, 28%); ¹H NMR (300 MHz, d₄-MeOH) δ8.07 (s, 1H), 7.74 (d, J=8.6 Hz, 2H), 7.35 (d, J=8.7 Hz, 2H), 7.19 (m,4H), 5.17 (d, J=6.6 Hz, 1H), 5.07 (d, J=6.5 Hz, 1H), 5.03 (d, J=6.7 Hz,1H), 4.93 (d, J=6.4 Hz, 1H), 3.64 (s, 2H), 3.12 (m, 2H), 2.95 (m, 2H),2.07 (s, 3H), 1.27 (s, 9H). LCMS-B: rt 5.80 min; 522.2 m/z [M+H]⁺.

(c)2-(2-(2-(2-(4-(3-Aminooxetan-3-yl)phenylamino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide(31)

TFA (0.5 mL) was added to a solution of2-(2-(2-(2-(4-(3-(1,1-dimethylethylsulfinamido)oxetan-3-yl)phenylamino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide(A122) (30 mg, 0.058 mmol) in DCM (3.0 mL) under a nitrogen atmosphereand the resulting mixture stirred at room temperature for 30 minutes,then at 35° C. overnight. The volatiles were evaporated under reducedpressure, keeping the temperature below 30° C. The resulting oil waspurified by semi preparative HPLC, to give the title compound 31 (5.0mg, 21%); ¹H NMR (300 MHz, d₄-MeOH) δ 8.24 (br s, 1H), 8.15 (s, 1H),7.85 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H), 7.22 (m, 4H), 5.13 (d,J=7.7 Hz, 2H), 4.97 (d, J=7.7 Hz, 2H), 3.67 (s, 2H), 3.16 (m, 2H), 3.00(m, 2H), 2.13 (s, 3H). LCMS: rt 4.72 min; m/z 418.2 [M+H]⁺.

Example 32 Synthesis of2-(2-(2-(2-((4-(azetidin-3-yl)phenyl)amino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide(32)

(a) tert-Butyl3-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate(A123)

A suspension of2-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide (K6)(0.150 g, 0.518 mmol), tert-butyl3-(4-aminophenyl)azetidine-1-carboxylate (A77) (0.141 g, 0.569 mmol),Pd(OAc)₂ (2.3 mg, 0.010 mmol), Cs₂CO₃ (0.506 g, 1.55 mmol) and Xantphos(11.9 mg, 0.021 mmol) in 1,4-dioxane (2 mL) was heated under microwaveirradiation at 100° C. for 1.5 hours. The resulting mixture was dryloaded onto silica gel and purified using silica gel columnchromatography (CombiFlash Rf, 12 g SiO₂ Cartridge, 0-5% MeOH in DCM) togive the title compound A123 as a light orange foam (0.087 g, 33%); ¹HNMR (300 MHz, CDCl₃) δ 8.12 (s, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.53 (s,1H), 7.26-7.28 (m, 6H), 5.59 (brs, 2H), 4.32 (t, J=8.7 Hz, 2H), 3.97(dd, J=6.0, 8.4 Hz, 2H), 3.70-3.76 (m, 3H), 3.08-3.13 (m, 2H), 2.90-2.98(m, 2H), 2.13 (s, 3H), 1.48 (s, 9H). LCMS-B: rt 7.208 min; m/z 502[M+H]⁺.

(b)2-(2-(2-(2-((4-(Azetidin-3-yl)phenyl)amino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide(32)

TFA (1 mL) was added to a solution of tert-butyl3-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate(A123) (0.087 g, 0.17 mmol) in DCM (3 mL) and the resulting mixturestirred at room temperature for 3 hours. The volatiles were removed invacuo then 2 M aqueous K₂CO₃ solution (5 mL) and water (15 mL) wereadded to the residue. The resulting suspension was sonicated for 1minute, filtered and the filter cake dried. The resulting residue waspurified by semi preparative HPLC to give the title compound 32 as alight tan solid (7.6 mg, 10%); ¹H NMR (300 MHz, d₄-MeOH) δ 8.12 (s, 1H),7.74 (d, J=8.6 Hz, 2H), 7.33 (d, J=8.6 Hz, 2H), 7.18-7.28 (m, 4H),4.31-4.39 (m, 2H), 4.19-4.27 (m, 3H), 3.66 (s, 2H), 3.13-3.18 (m, 2H),2.96-3.01 (m, 2H), 2.12 (s, 3H). LCMS-B: rt 4.725 min; m/z 402 [M+H]⁺.

Example 33 Synthesis of2-(2-(2-(5-Methyl-2-((1-(piperidin-4-yl)-¹H-pyrazol-4-yl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(33)

tert-Butyl 4-(4-amino-¹H-pyrazol-1-yl)piperidine-1-carboxylate (A124)

Diisopropyl azodicarboxylate (3.60 mL, 18.3 mmol) was added dropwise toa solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (A110) (2.45g, 12.2 mmol), 4-nitro-¹H-pyrazole (1.38 g, 12.2 mmol) and PPh₃ (4.79 g,18.3 mmol) in THF (25 mL) at 0° C. The resulting mixture was maintainedat this temperature for 10 minutes and then warmed to room temperatureat which it was stirred for 6 days. The mixture was diluted with hexanes(80 mL) and EtOAc (20 mL) and stirred for 5 hours at room temperaturebefore filtering, washing the filter cake with hexanes (50 mL) andconcentrating the filtrate in vacuo. The resulting oil was purified bysilica gel column chromatography (Biotage Isolera, 2×40 g SiO₂cartridges, 0-50% EtOAc in cyclohexane) to give a residue that wasdissolved in EtOH (200 mL). 10% Pd/C (53% water; 0.500 g) was added andthe resulting suspension stirred under an atmosphere of hydrogen at roomtemperature for 18 hours. The mixture was filtered through Celite,washing with EtOAc (ca. 100 mL) and then the filtrate was concentratedunder reduced pressure. The resulting oil was dissolved in EtOAc (200mL) and washed with water (2×100 mL) and then aqueous 2 M HCl (100 mL).The acidic layer was basified with aqueous 2 M NaOH to pH 13 andextracted with EtOAc (2×100 mL). The combined organic layers from thebasified extraction were washed with brine (50 mL), dried (Na₂SO₄),filtered and concentrated under reduced pressure to give the titlecompound A124 as a purple oil (1.39 g, 34%); ¹H NMR (400 MHz, CDCl₃) δ7.15 (d, J=0.9 Hz, 1H), 7.02 (d, J=0.9 Hz, 1H), 4.20 (s, 2H), 4.11 (m,1H), 2.95-2.76 (m, 4H), 2.11-2.02 (m, 2H), 1.83 (qd, J=12.3, 4.5 Hz,2H), 1.46 (s, 9H).

(b) tert-Butyl4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-methylpyrimidin-2-yl)amino)-¹H-pyrazol-1-yl)piperidine-1-carboxylate(A125)

A suspension of methyl2-(2-((2-chloro-5-methylpyrimidin-4-yl)ethynyl)phenyl)acetate (K7)(0.100 g, 0.333 mmol), tert-butyl4-(4-amino-¹H-pyrazol-1-yl)piperidine-1-carboxylate (A124) (0.089 g,0.333 mmol), Cs₂CO₃ (0.433 g, 1.33 mmol), Pd₂(dba)₃ (0.030 g, 0.033mmol) and Xantphos (0.058 g, 0.100 mmol) in 1,4-dioxane (6 mL) wasdegassed with nitrogen for 5 minutes before heating under microwaveirradiation for 30 minutes at 120° C. The resulting mixture was dilutedwith EtOAc (100 mL) and washed with water (2×25 mL), brine (25 mL),dried (Na₂SO₄) then concentrated under reduced pressure. The resultingbrown oil was purified by silica gel column chromatography (BiotageIsolera, 24 g SiO₂ cartridge, 0-100% EtOAc in hexanes) to give the titlecompound A125 as a yellow foam (0.096 g, 54%); ¹H NMR (400 MHz, CDCl₃) δ8.21 (s, 1H), 7.89 (s, 1H), 7.57 (dd, J=7.6, 1.3 Hz, 1H), 7.44 (s, 1H),7.36-7.22 (m, 2H), 7.19 (s, 1H), 6.87 (s, 1H), 4.22-4.12 (m, 3H), 3.88(s, 2H), 3.62 (s, 3H), 2.82 (t, J=11.9 Hz, 2H), 2.26 (s, 3H), 2.11-2.02(m, 2H), 1.89 (qd, J=12.4, 4.4 Hz, 2H), 1.40 (s, 9H). LCMS-A: rt 6.358min; m/z 531 [M+H]⁺.

(c) tert-Butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)-¹H-pyrazol-1-yl)piperidine-1-carboxylate(A126)

A suspension of 10% Pd/C (53% water; 0.020 g) and tert-butyl4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-methylpyrimidin-2-yl)amino)-¹H-pyrazol-1-yl)piperidine-1-carboxylate(A125) (0.092 g, 0.17 mmol) in DMF (5 mL) and Et₃N (0.5 mL) was stirredat room temperature for 18 hours under a hydrogen atmosphere. Theresulting mixture was filtered through Celite, and the filter cakewashed with EtOAc (250 mL). The combined filtrates were washed withwater (3×100 mL) and brine (3×100 mL). The organic layer was dried(Na₂SO₄), filtered and concentrated under reduced pressure. Theresulting oil was purified by silica gel column chromatography (BiotageIsolera, 40 g SiO₂ cartridge, 0-100% EtOAc in hexanes) to give the titlecompound A126 as a pale brown oil (80 mg, 86%); ¹H NMR (400 MHz, CDCl₃)δ 8.06 (s, 1H), 7.89 (s, 1H), 7.51 (d, J=0.4 Hz, 1H), 7.25-7.15 (m, 4H),6.92 (s, 1H), 4.31-4.15 (m, 3H), 3.70 (s, 2H), 3.66 (s, 3H), 3.08 (dd,J=9.4, 6.3 Hz, 2H), 2.90 (dd, J=9.5, 6.3 Hz, 4H), 2.15-2.07 (m, 2H),2.05 (s, 3H), 2.00-1.85 (m, 2H), 1.46 (s, 9H). LCMS-A: rt 6.195 min; m/z535.3 [M+H]⁺.

(d)2-(2-(2-(2-((1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-¹H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)ethyl)phenyl)aceticacid (A127)

LiOH.H₂O (0.302 g, 7.20 mmol) was added to a solution of tert-butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)-¹H-pyrazol-1-yl)piperidine-1-carboxylate(A126) (0.077 g, 0.14 mmol) in H₂O (1 mL) and THF (10 mL) and theresulting mixture was heated to 40° C. for 18 hours. The volatiles wereremoved in vacuo and the residue was diluted with EtOAc (100 mL), washedwith aqueous 2 M HCl (50 mL), water (100 mL), brine (50 mL) and driedover MgSO₄. The volatiles were removed in vacuo to give the titlecompound A127 as a pale yellow solid (0.068 g, 91%); LCMS-A: rt 5.366min; m/z 521 [M+H]⁺.

(e) tert-Butyl4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)-¹H-pyrazol-1-yl)piperidine-1-carboxylate(A128)

HOBt (0.051 g, 0.379 mmol), EDCl.HCl (0.081 g, 0.42 mmol) and DIPEA(0.11 mL, 0.65 mmol) were added to a solution of2-(2-(2-(2-((1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-¹H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-ylethyl)phenyl)aceticacid (A127) (0.068 g, 0.131 mmol) in dry DMF (5 mL) under an atmosphereof nitrogen. After 10 minutes ammonium carbonate (0.126 g, 1.31 mmol)was added in one portion and the resulting mixture stirred for 18 hoursat room temperature. Additional HOBt (0.051 g, 0.38 mmol), EDCl.HCl(0.081 g, 0.42 mmol), DIPEA (0.11 mL, 0.65 mmol) and ammonium carbonate(0.126 g, 1.31 mmol) were added to the reaction mixture and the mixturestirred for 12 days at room temperature. The volatiles were removed invacuo then the residue diluted with EtOAc (50 mL) and washed withsaturated aqueous NaHCO₃ (50 mL). The aqueous layer was extracted withEtOAc (2×25 mL). The combined organic layers were washed with brine (25mL) and dried over Na₂SO₄. The solvent was removed in vacuo to afford ayellow oil that was purified by silica gel column chromatography(Biotage Isolera, 25 g SiO₂ cartridge, 0-100% EtOAc in petroleum benzine40-60° C. followed by 0-30% MeOH in EtOAc) to give the title compoundA127 as an off white solid (0.044 g, 65%); ¹H NMR (400 MHz, CDCl₃) δ8.05 (s, 1H), 7.85 (s, 1H), 7.50 (d, J=0.5 Hz, 1H), 7.26-7.17 (m, 5H),5.79 (s, 1H), 5.62 (s, 1H), 4.26-4.19 (m, 3H), 3.65 (s, 2H), 3.07 (dd,J=9.5, 6.2 Hz, 2H), 2.93-2.82 (m, 4H), 2.15-2.08 (m, 2H), 2.04 (s, 3H),1.91 (qd, J=12.3, 4.3 Hz, 2H), 1.46 (s, 9H). LCMS-A: rt 5.178 min; m/z520 [M+H]⁺.

(f)2-(2-(2-(5-methyl-2-((1-(piperidin-4-yl)-¹H-pyrazol-4-yl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(33)

TFA (0.5 mL) was added to a solution of tert-butyl4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)-¹H-pyrazol-1-yl)piperidine-1-carboxylate(A128) (0.040 g, 0.077 mmol) in DCM (5 mL) and the resulting mixturestirred for 18 hours at room temperature. The volatiles were evaporatedunder reduced pressure and the residue partitioned between 2 M NaOH (10mL) and EtOAc (25 mL). The organic layer was separated and washed withwater (25 mL), brine (25 mL), dried (Na₂SO₄) and concentrated underreduced pressure to give the title compound 33 as an off white solid(0.015 g, 49%); ¹H NMR (400 MHz, d₄-MeOH) δ 8.05 (s, 1H), 7.99 (d, J=0.5Hz, 1H), 7.56 (d, J=0.6 Hz, 1H), 7.27-7.22 (m, 1H), 7.22-7.15 (m, 3H),4.23 (tt, J=11.7, 4.1 Hz, 1H), 3.64 (s, 2H), 3.23-3.09 (m, 4H),3.02-2.91 (m, 2H), 2.76 (td, J=12.8, 2.5 Hz, 2H), 2.14-2.05 (m, 5H),1.98-1.85 (m, 2H). LCMS-A: rt 3.968 min; m/z 420 [M+H]⁺.

Example 34 Synthesis of2-(2-(2-(2-((4-(1-aminoethyl)phenyl)amino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide(34)

(a) 1-(4-Nitrophenyl)ethanamine (A129)

A suspension of 4′-nitroacetophenone (5.00 g, 30.3 mmol) and ammoniumacetate (28.4 g, 378 mmol) in MeOH (75 mL) was stirred at roomtemperature for 20 minutes. Sodium cyanoborohydride (1.38 g, 21.2 mmol)was added and the resulting mixture stirred for 48 hours. Aqueous HCl (6M, 40 mL) was added and the mixture was filtered. The filtrate waswashed with Et₂O (3×40 mL) then the aqueous phase was basified to pH 10using KOH. The basified aqueous layer was extracted with DCM (3×30 mL)and the combined organic phases were dried (MgSO₄), filtered andevaporated in vacuo to give the title compound A129 as an amorphousorange solid (3.00 g, 60%); ¹H NMR (300 MHz, CDCl₃) δ 8.22 (d, J=8.6 Hz,2H), 7.57 (d, J=8.6 Hz, 2H), 4.27-4.33 (m, 1H), 2.20 (brs, 2H), 1.45 (d,J=6.6 Hz, 3H).

(b) tert-Butyl (1-(4-nitrophenylethyl)carbamate (A130)

A solution of di-tert-butyl dicarbonate (3.94 g, 18.1 mmol) in DCM (50mL) was slowly added over 1 hour by syringe pump to a solution of1-(4-nitrophenyl)ethanamine (A129) (3.00 g, 18.05 mmol) and Et₃N (3.77mL, 27.1 mmol) in DCM (120 mL). The resulting mixture was then stirredat room temperature for 20 hours. Water (50 mL) was added and themixture extracted with DCM (×2). The combined organic extracts werewashed with water, brine, dried (Na₂SO₄), filtered and the volatilesremoved in vacuo. The residue was purified using silica gel columnchromatography (CombiFlash Rf, 120 g SiO₂ cartridge, 10-20% EtOAc incyclohexane) to give the title compound A130 as a white solid (3.78 g,78%); ¹H NMR (300 MHz, CDCl₃) δ 8.21 (d, J=8.6 Hz, 2H), 7.47 (d, J=8.7Hz, 2H), 4.87 (s, 2H), 1.38-1.58 (m, 12H).

(c) tert-Butyl (1-(4-aminophenyl)ethyl)carbamate (A131)

A suspension of 10% Pd/C (1.25 g) and tert-butyl(1-(4-nitrophenyl)ethyl)carbamate (A130) (3.78 g, 14.2 mmol) in EtOAc(50 mL) was stirred under a hydrogen atmosphere for 3 hours. Theresulting solution was filtered through a pad of Celite, washing withEtOAc, then the filtrate was concentrated in vacuo to give the titlecompound A131 as a viscous oil (3.01 g, 89%); ¹H NMR (300 MHz, CDCl₃) δ7.11 (d, J=8.1 Hz, 2H), 6.70 (d, J=8.0 Hz, 2H), 4.70 (brs, 2H), 1.44 (m,14H). LCMS-B: 4.444 min; m/z 237 [M+H]⁺.

(d) tert-Butyl(1-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)ethyl)carbamate(A132)

A suspension of2-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide (K6)(0.200 g, 0.690 mmol), tert-butyl (1-(4-aminophenyl)ethyl)carbamate(A131) (0.326 g, 1.38 mmol), Pd(OAc)₂ (3 mg, 0.01 mmol), Cs₂CO₃ (0.675g, 2.07 mmol) and Xantphos (16 mg, 0.028 mmol) in 1,4-dioxane (3 mL) washeated under microwave irradiation at 105° C. for 6 hours. The resultingmixture was filtered through a plug of silica gel, washing with 20% MeOHin K1 DCM and then the volatiles evaporated in vacuo. The residue waspurified using silica gel column chromatography (CombiFlash Rf, 12 gSiO₂ Cartridge, 5-80% EtOAc in cyclohexane) to give the title compoundA132 as a white solid (0.099 g, 29%); LCMS-B: rt 6.832 min; m/z 490[M+H]⁺.

A137

(e)2-(2-(2-(2-((4-(1-Aminoethyl)phenyl)amino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide(34)

TFA (1 mL) was added to a solution of tert-butyl(1-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)ethyl)carbamate(A132) (0.099 g, 0.20 mmol) in DCM (5 mL) and the resulting mixturestirred at room temperature for 3 hours. The volatiles were evaporatedunder reduced pressure then 2 M aqueous K₂CO₃ solution (10 mL) and water(15 mL) were added to the residue. The resulting suspension wassonicated for 1 minute, filtered and the filter cake dried to give thetitle compound 34 as a light tan solid (77 mg, 97%); ¹H NMR (300 MHz,d₆-DMSO) δ 9.26 (s, 1H), 8.15 (s, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.42 (s,1H), 7.23 (d, J=8.6 Hz, 2H), 7.14-7.23 (m, 4H), 6.92 (s, 1H), 3.92 (d,J=6.4 Hz, 1H), 3.50 (s, 2H), 3.32 (brs, 2H), 3.02-3.07 (m, 2H),2.88-2.90 (m, 2H), 2.06 (s, 3H), 1.23 (d, J=6.5 Hz, 3H). LCMS-B: rt4.691 min; m/z 390 [M+H]⁺.

Example 352-(2-(2-(2-((1-(piperidin-4-yl)-¹H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide

(a) tert-Butyl4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-¹H-pyrazol-1-yl)piperidine-1-carboxylate(A133)

A 1.0 M solution of ZnCl₂ in diethyl ether (20.7 mL, 20.7 mmol) wasadded to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (4.48g, 20.7 mmol) in t-BuOH (100 mL) and DCE (100 mL). The mixture wasstirred for 10 minutes then diluted with t-BuOH (100 mL) and DCE (100mL) before tert-butyl4-(4-amino-¹H-pyrazol-1-yl)piperidine-1-carboxylate (5.00 g, 18.8 mmol)and Et₃N (10.4 mL) were added. The mixture was stirred at roomtemperature overnight, the volatiles were removed in vacuo and theresultant residue was suspended in water (500 mL) and sonicated for 15minutes. The solid was isolated by vacuum filtration and the filter cakewashed with water (100 mL) and acetone (25 mL) to give the titlecompound (A133) as a tan solid (5.92 g, 71%); LCMS-A: rt 6.895 min; m/z445.1 [M−H]⁻.

(b) tert-butyl4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-¹H-pyrazol-1-yl)piperidine-1-carboxylate(A134)

A suspension of tert-butyl4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-¹H-pyrazol-1-yl)piperidine-1-carboxylate(A133) (700 mg, 1.57 mmol), K1 (300 mg, 1.72 mmol), PPh₃ (21 mg, 0.078mmol) and CuI (15 mg, 0.078 mmol) in Et₃N (1 mL) and DMF (4 mL) wassonicated for 10 minutes before PdCl₂(PPh₃)₂ (55 mg, 0.078 mmol) wasadded. The reaction mixture was irradiated in the microwave at 120° C.for 40 minutes. The resultant mixture was adsorbed onto silica gel andpurified by column chromatography (Biotage Isolera, 40 g SiO₂ cartridge,0-100% EtOAc in petroleum benzine 40-60° C.), a second silica gel columnwas run (Biotage Isolera, 40 g SiO₂ cartridge, 0-50% EtOAc in petroleumbenzine 40-60° C.) to give the title compound (A134) as a yellow solid(392 mg, 43%). LCMS-A: rt 7.064 min; m/z 585 [M+H]⁺.

(c) tert-Butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-¹H-pyrazol-1-yl)piperidine-1-carboxylate(RCF—013—72_A) (A135)

A solution of tert-butyl4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-¹H-pyrazol-1-yl)piperidine-1-carboxylate(A134) (392 mg, 0.671 mmol) in EtOAc (40 mL) and DMF (2 mL) was stirredwith 10% Pd/C (wetted with ca. 53% water, 100 mg) under a hydrogenatmosphere at room temperature overnight. The mixture was filteredthrough Celite and the filter cake was washed with EtOAc (50 mL). Thevolatiles were removed in vacuo and the resulting yellow oil wasadsorbed onto silica gel and purified by silica gel columnchromatography (Biotage Isolera, 40 g SiO₂ cartridge, 0-100% EtOAc inpetroleum benzine 40-60° C. then 0-20% MeOH in EtOAc) to give the titlecompound (A135) as a yellow solid (300 mg, 76%), ¹H NMR (400 MHz,Chloroform-d) δ 8.44 (s, 1H), 7.85 (s, 1H), 7.64-7.46 (m, 1H), 7.22-7.06(m, 4H), 4.32-4.04 (m, 3H), 3.67 (s, 2H), 3.60 (s, 3H), 3.14-2.94 (m,4H), 2.87-2.75 (m, 2H), 2.14-1.99 (m, 2H), 1.97-1.79 (m, 2H), 1.40 (s,9H).

(d)2-(2-(2-(2-((1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-¹H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)aceticacid (A136)

A mixture of tert-butyl4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-¹H-pyrazol-1-yl)piperidine-1-carboxylate(A135) (300 mg, 0.510 mmol) and LiOH.H₂O (855 mg, 20.4 mmol) in THF (20mL) and H₂O (1 mL) was stirred at 40° C. overnight. The mixture wasdiluted with DCM (50 mL) and water (50 mL) and the aqueous layer wasextracted with EtOAc (2×50 mL). The combined washings were dried(Na₂SO₄) and the volatiles were removed in vacuo to yield the titlecompound (A136) as a yellow oil (270 mg, 92%). LCMS-A: rt 6.679 min; m/z575.2 [M+H]⁺.

(e) tert-Butyl4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-¹H-pyrazol-1-yl)piperidine-1-carboxylate(A137)

Ammonium carbonate (903 mg 9.40 mmol) was added to a suspension of2-(2-(2-(2-((1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-¹H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)aceticacid (A136) (270 mg, 0.470 mmol), HOBt (317 mg, 2.35 mmol) and EDCl.HCl(450 mg, 2.35 mmol) in Et₃N (1.0 mL) and DMF (25 mL) and the resultingsolution was stirred at 40° C. overnight. The volatiles were removed invacuo and the resulting residue was dissolved in EtOAc (250 mL) andwashed with water (250 mL). The organics were adsorbed onto silica geland the product was purified by silica gel column chromatography(Biotage Isolera, 40 g SiO₂ cartridge, 0-100% EtOAc in petroleum benzine40-60° C., then 0-20% MeOH in EtOAc) to yield the title compound (A137)as a white solid (171 mg, 63%). LCMS-A: rt 6.481 min; m/z 574.3 [M+H]⁺.

(f)2-(2-(2-(2-((1-(Piperidin-4-yl)-¹H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(35)

TFA (2 mL) was added to a solution of tert-butyl4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-¹H-pyrazol-1-yl)piperidine-1-carboxylate(A137) (171 mg, 0.298 mmol) in DCM (25 mL) and the mixture was stirredat room temperature overnight. The volatiles were removed in vacuo andthe resultant solid was dissolved in CHCl₃ (1 mL). Cyclohexane (25 mL)was added and the resultant precipitate was removed by filtration,washed with cyclohexane (25 mL) and air dried to yield the titlecompound as a white solid (101 mg, 72%). LCMS-A: rt 4.717 min; m/z 474.2[M+H]⁺.

Example 36 Synthesis of2-(2-(2-(2-((1-(1-methylpiperidin-4-yl)-¹H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(36)

2-(2-(2-(2-((1-(1-Methylpiperidin-4-yl)-¹H-pyrazol-4-yl)-amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(36)

NaHB(OAc)₃ (147 mg, 0.693 mmol) was added cautiously to a stirredsolution of2-(2-(2-(2-((1-(piperidin-4-yl)-¹H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(35) (82 mg, 0.17 mmol) in 37% aqueous formaldehyde solution (39 μL,0.52 mmol) and MeOH (5.0 mL). The reaction mixture was stirred for 1 hrand then quenched with water (50 mL). The resultant precipitate wasremoved by filtration, washed with cyclohexane and dried under highvacuum to yield the title compound as a white solid (82 mg, 97%).LCMS-A: rt 4.751 min; m/z 488.3 [M+H]⁺.

Example 37 Synthesis of2-(2-(2-(2-(4-(1-aminoethyl)phenylamino)-5-chloropyrimidin-4-yl)ethyl)phenyl)acetamide(37)

(a) 2-(2-((2,5-Dichloropyrimidin-4-yl)ethynyl)phenyl)acetamide (A138)

To a solution of 18 (0.75 g, 4.7 mmol) and 2,4,5-trichloropyrimidine(0.70 mL, 6.1 mmol) in 1,4-dioxane (10 mL) and Et₃N (2.6 mL, 19 mmol)containing CuI (0.018 g, 0.094 mmol) was added PdCl₂(PPh₃)₂ (0.033 g,0.047 mmol). The reaction mixture was heated at 70° C. for 2 hours undera nitrogen atmosphere. The solvent was removed in vacuo and the residuewas diluted with 20% diethyl ether in cyclohexane. The precipitate wasfiltered, washed with water and dried in vacuo to give the titlecompound (A138) as a light brown solid (1.22 g, 85%). LCMS-C: rt 4.88min; m/z 306 [M+H]⁺.

(b) 2-(2-(2-(2,5-Dichloropyrimidin-4-yl)ethyl)phenyl)acetamide (A139)

A solution of 2-(2-((2,5-dichloropyrimidin-4-yl)ethynyl)phenyl)acetamide(A138) (1.2 g, 4.0 mmol) in DMF (40 mL) and MeOH (8 mL) was stirred withplatinum(II)oxide (0.27 g, 1.2 mmol) under an atmosphere of hydrogen for144 hours at ambient temperature. The reaction mixture was diluted withEtOAc and filtered through a plug of Celite. The solvents were removedin vacuo and the crude residue was purified by silica gel columnchromatography (Combiflash Rf, 0-10% MeOH in DCM) to give the titlecompound (A139) as a light yellow solid (0.63 g, 51%). LCMS-C: rt 4.82min; m/z 310 [M+H]⁺.

(c) tert-Butyl1-(4-(4-(2-(2-amino-2-oxoethyl)phenethyl)-5-chloropyrimidin-2-ylamino)phenyl)ethylcarbamate(A140)

A mixture of 2-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)acetamide(A139) (0.050 g, 0.16 mmol), (A131) (0.046 g, 0.19 mmol), Xantphos(0.014 g, 0.024 mmol) and Cs₂CO₃ (0.16 g, 0.48 mmol) in 1,4-dioxane (1mL) was bubbled with nitrogen for 10 minutes. Palladium (II) acetate(0.0036 g, 0.016 mmol) was added and the mixture was heated at 90° C.under microwave irradiation for 90 minutes. The mixture was portionedbetween water and EtOAc. The layers were separated and the water layerwas extracted with EtOAc (twice). The combined organic extracts werewashed with brine, dried (Na₂SO₄) and the solvent evaporated in vacuo togive the crude product. Purification by silica gel column chromatography(3 times) (Combiflash Rf, 0-10% MeOH in DCM twice then 0-100% EtOAc incyclohexane) to give the title compound (A140) as a colourless oil(0.007 g, 9%). LCMS-C: rt 5.54 min; m/z 510 [M+]⁺

(d)2-(2-(2-(2-(4-(1-Aminoethyl)phenylamino)-5-chloropyrimidin-4-yl)ethyl)phenyl)acetamide(37)

To a solution of tert-butyl1-(4-(4-(2-(2-amino-2-oxoethyl)phenethyl)-5-chloropyrimidin-2-ylamino)phenyl)ethylcarbamate(A140) (0.0070 g, 0.014 mmol) in DCM (1 mL) was added TFA (0.50 mL). Themixture was stirred at ambient temperature for 2 hours before thevolatiles were removed in vacuo. The crude residue was purified using anSCX cartridge, (MeOH then 2 N ammonia in EtOH eluent) to give the titlecompound (37) as a grey solid (0.005 g, 89%). LCMS-C: rt 4.29 min; m/z410 [M+]⁺

Example 38 Synthesis of2-(2-(2-(2-((3-(1-aminoethyl)phenyl)amino)-5-chloropyrimidin-4-yl)ethyl)phenyl)acetamide(38)

(a)2-(2-(2-(2-((3-Acetylphenyl)amino)-5-chloropyrimidin-4-ylethyl)phenyl)acetamide(A141)

A solution of 2-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)acetamide (A139) (0.158 g, 0.509 mmol) in 2-propanol (2 mL)containing 1-(3-aminophenyl)ethanone (0.138 g, 1.01 mmol) was heatedunder microwave irradiation at 150° C. for 2 hours. The reaction mixturewas adsorbed onto silica gel and the product was purified using silicagel column chromatography (CombiFlash Rf, 12 g SiO₂ Cartridge, 10-65%EtOAc in cyclohexane) to give the title compound (A141) as a white solid(0.125 g, 60%). LCMS-B: rt 6.804 min; m/z 409 [M+H]⁺.

(b)2-(2-(2-(2-((3-(1-Aminoethyl)phenyl)amino)-5-chloropyrimidin-4-yl)ethyl)phenyl)acetamide (38)

Ammonium acetate (0.339 g, 4.40 mmol) was added to a solution of2-(2-(2-(2-((3-acetylphenyl)amino)-5-chloropyrimidin-4-yl)ethyl)phenyl)acetamide(A141) (0.120 g, 0.293 mmol) in MeOH (5 mL) and the mixture was stirredfor 20 minutes under a nitrogen atmosphere. Sodium cyanoborohydride(0.013 g, 0.21 mmol) was added and the mixture was stirred for 6 hours.Additional sodium cyanoborohydride (0.013 g, 0.21 mmol) was added andthe mixture was stirred for 16 hours at room temperature. The mixturewas diluted with water (10 mL), acidified with 20% aqueous HCl (10 mL)and washed with Et₂O (2×30 mL). The aqueous phase was basified withsolid potassium hydroxide to pH 10 and extracted with DCM (3×30 mL). Thecombined organic phases were washed with water, brine, dried (Na₂SO₄)and the solvent evaporated in vacuo. The crude product was adsorbed ontosilica gel and purified by column chromatography (CombiFlash Rf, 12 gSiO₂ Cartridge, 0-30% MeOH in DCM) to give the title compound (38) as awhite foam (0.057 g, 47%). LCMS-B: rt 5.45 min; m/z 410 [M+H]⁺.

Example 39 Synthesis of2-(2-(2-(2-((3-(1-acetamidoethyl)phenyl)amino)-5-chloropyrimidin-4-yl)ethyl)phenyl)acetamide(39)

A solution of2-(2-(2-(2-((3-(1-aminoethyl)phenyl)amino)-5-chloropyrimidin-4-yl)ethyl)phenyl)acetamide(38) (0.045 g, 0.11 mmol) in pyridine (3 mL) containing acetic anhydride(62 μL, 0.66 mmol) and 4-dimethylaminopyridine (2.6 mg, 0.022 mmol) wasstirred at room temperature for 22 hours under a nitrogen atmosphere.The mixture was acidified with 1 M hydrochloric acid (30 mL) andextracted with DCM (3×20 mL). The combined organic phases were washedwith water, brine, dried (Na₂SO₄) and the solvent evaporated in vacuo.The crude product was adsorbed onto silica gel and the product waspurified by column chromatography (CombiFlash Rf, 4 g SiO₂ Cartridge,0-10% MeOH in DCM) to yield the title compound (39) as a white solid(0.035 g, 70%). LCMS-B: rt 6.20 min; m/z 452 [M+H]⁺.

Example 40 Synthesis of2-(2-(2-(2-((6-(1-aminoethyl)pyridin-3-yl)amino)-5-chloropyrimidin-4-yl)ethyl)phenyl)acetamide(40)

(a)1-(5-((4-Chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)ethanone(A141)

A suspension of 1-(5-aminopyridin-2-yl)ethanone (2.08 g, 15.3 mmol) inDMF (30 mL) and DIPEA (6.65 mL, 38.2 mmol) was stirred at roomtemperature for 15 minutes. 2,4-Dichloro-5-(trifluoromethyl)pyrimidine(2.47 mL, 18.33 mmol) was added in 4 portions over 5 minutes. Thereaction mixture was stirred at 60° C. for 2 hours under a nitrogenatmosphere before it was diluted with water and EtOAc. The aqueous wasextracted several times with EtOAc and the combined organic phases werewashed with water, brine, dried (Na₂SO₄), filtered and the solventevaporated in vacuo. The crude product was adsorbed onto silica gel andpurified by column chromatography (CombiFlash Rf, 40 g SiO₂ Cartridge,0-30% EtOAc in cyclohexane) to give 2.17 g of a white solid. The 1:1regiosiomeric mixture was dissolved in a minimum volume of cold (5° C.)acetonitrile (4-8 mL), sonicated for 10 seconds then filtered and driedto give the title compound (A141) as a white solid (1.14 g, 23%).LCMS-B: rt 7.34 min; m/z 317 [M+H]⁺.

(b)2-(2-((2-((6-Acetylpyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetamide(A142)

1-(5-((4-Chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)ethanone(A141) (0.313 g, 0.988 mmol) and I8 (0.189 g, 1.18 mmol) were added to asolution of PdCl₂(PPh₃)₂ (0.017 g, 0.025 mmol), CuI (0.010 g, 0.049mmol) and PPh₃ (0.013 g, 0.049 mmol) in DMF (3 mL) and Et₃N (0.552 mL,3.95 mmol). The reaction mixture was heated under microwave irradiationat 120° C. for 15 minutes. The reaction mixture was diluted with waterand then filtered. The solid was washed with water and dried beforebeing suspended in EtOAc, ultra sonicated for 20 seconds, filtered anddried to give the title compound (A142) as a light brown solid (0.347 g,79%). LCMS-B: rt=6.78 min; m/z=440 [M+H]⁺.

(c)2-(2-(2-(2-((6-Acetylpyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(A143)

A solution of2-(2-((2-((6-acetylpyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetamide(A142) (0.347 g, 0.790 mmol) in DMF (20 mL), EtOH (3 mL) and Et₃N (1 mL)containing 10% palladium on carbon (0.110 g) was stirred under ahydrogen atmosphere for 20 hours. The reaction mixture was filteredthrough a pad of Celite and the solvent was concentrated in vacuo. Thecrude material was adsorbed onto silica gel and purified by silica gelcolumn chromatography (CombiFlash Rf, 24 g SiO₂ Cartridge, 0-10% MeOH inDCM) to give the title compound (A143) as a white solid (0.200 g, 57%).LCMS-B: 6.80 min; m/z 444 [M+H]⁺.

(d)2-(2-(2-(2-((6-(1-Aminoethyl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(40)

Ammonium acetate (0.250 g, 3.23 mmol) was added to a solution of2-(2-(2-(2-((6-acetylpyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(A143) (0.072 g, 0.162 mmol) in MeOH (4 mL) and THF (2 mL) and themixture was stirred for 20 minutes under a nitrogen atmosphere. Sodiumcyanoborohydride (7 mg, 0.1 mmol) was added and the mixture was stirredfor 5 hours. Additional sodium cyanoborohydride (7 mg, 0.1 mmol) wasadded and the mixture was stirred for a total of 22 hours at 35° C. Theaqueous phase was basified with solid potassium hydroxide (pH 10) andextracted with EtOAc (3×30 mL). The combined organic phases were washedwith brine, dried (Na₂SO₄), and adsorbed on to silica. The product waspurified by silica column chromatography (CombiFlash Rf, 12 g SiO₂Cartridge, 0-20% MeOH in DCM) to give the title compound (40) as a whitesolid (0.042 g, 58%). LCMS-B: 4.30 min; m/z 445 [M+H]⁺.

Biological Assays

The activity of compounds of the invention can be profiled usingbiochemical and cellular assays. Primary potency at VEGFR3 can beassessed using an Alpha Screen™ technology biochemical assay. Theability of compounds of the invention to inhibit VEGFR3 within cells canbe assessed with an ELISA type assay.

VEGFR3 Biochemical Assay

Compounds of the invention may be tested for in vitro activity in thefollowing assay: A biotin labelled peptide is used as substrate (aminoacid sequence:Biotin-Glu-Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH₂).VEGFR3 cytoplasmic domain (amino acids 798-1298) was purchased asN-terminal GST-fusion protein (“the enzyme”). The 15 μL assay reactionsare run in Greiner brand white 384-well low volume plates. All reactionscontained 10 mM HEPES pH 7.4, 10 mM MgCl₂, 0.01% (v/v) Tween-20, 50 μMNa₃VO₄, 0.01% (w/v) albumin from chicken egg white, 1 mM Dithiothreitol,111 nM peptide substrate, 500 μM ATP, and 3.8 ng/reaction enzyme, withthe enzyme being omitted from negative control reactions. Compounds wereadded in a volume of 100 mL from dilution series prepared in DMSO,positive and negative control reactions receiving the same volume DMSOwithout compound. The plates were sealed with adhesive seals andincubated for 90 minutes at 30 degree Celsius. The reactions werestopped with the detection reagents added at the same time as follows:Product formation was quantified as amplified luminescence betweenPerkinElmer AlphaScreen™ beads, using Streptavidin-coated donor andanti-phosphotyrosine (P-Tyr-100) acceptor beads. To each reaction, 5 μLcontaining 10 mM HEPES pH 7.4, 25 mM NaCl, 100 mM EDTA, 0.01% (v/v)Tween-20, and 6.25 μg/mL of each bead type were added. Plates wereincubated for 6 hours before being read on a PerkinElmer EnVision™ platereader in HTS Alphascreen™ mode. IC₅₀ values were obtained bycalculating percent inhibition (% I) for each reaction relative tocontrols on the same plate (% I=(I-CN)/(CP-CN) where CN/CP are theaverages of the negative/positive reactions, respectively), then fittingthe % I data vs. compound concentration [I] to %I=(A+((B−A)/(1+((C/[I])̂D)))) where A is the lower asymptote, B is theupper asymptote, C is the IC₅₀ value, and D is the slope factor.

The above assay was also run in a modified form in some cases (indicatedbelow with *). In these cases, VEGFR3 cytoplasmic domain (amino acids818-1177, lacking 949-1002 of UniProt accession number P35916) wasexpressed and purified as N-terminal Hexa-His-fusion protein (“theenzyme”), rather than using the N-terminal GST-fusion protein. The assayconditions were the same as above but with 1 μM ATP and 8 ng/reaction ofthe enzyme. The comparable performance of both assay versions wasmonitored using benchmark compounds as described in the literature.

VEGFR3 Biochemical Assay Results

Compound IC₅₀ (nM) 1 161 2 39 3 97 4 35 5 28 6 23 7 40 8 34 9 68 10 7611 26 12 20 13 67 14 81 15 31 16 22 17 67 18 46 19 70 20 37 21 44 22 10123 72 24 34 25 278 26 24 27 118 28 24 29 17 30 9 31 23 32 52 33 28 34 7135 23 36 50 37 12 38 76 39 10 40 187 41 26

VEGFR3 Phospho ELISA Assay

Compounds of the invention may be tested for in vitro activity in thefollowing assay:

Adult human dermal lymphatic microvascular endothelial cells(HMVEC-dLyAD) (Cat#CC-2810, Lonza) were seeded into clear-bottom, TCtreated 12 well plates (Cat #665180, Greiner Bio-One) in EGM-2MV(Cat#CC-3202, Lonza) at 180,000 cells/well (volume 1 mL), and the platesincubated at 37° C. and 5% CO₂ for 6 hours. The media was replaced withEBM-2 (Cat #CC-3156, Lonza)+0.1% BSA (Cat#A8412, Sigma) and cellsincubated for a further period (overnight at 37° C. and 5% CO₂).

96 well Maxisorp immuno plates (Cat #439454, Nunc) were coated with 100μL of Total VEGFR3 capture antibody (Part #841888, Human TotalVEGFR3/FLT4 ELISA Kit, Cat #DYC3491, R&D Systems), or Phospho VEGFR3Capture antibody (Part #841885, Human Phospho VEGFR3/FLT4 ELISA Kit,Cat#DYC2724, R&D Systems). The plates were covered and incubated at roomtemperature overnight.

The coating antibody was flicked out and the plates washed three timeswith Wash Buffer (Phosphate buffered saline (137 mM NaCl, 2.7 nM KCl,8.1 nM Na₂HPO₄, 1.5 mL KH₂PO₄, pH 7.2-7.4), 0.05% Tween 20). 300 μL ofblocking buffer (5% v/v Tween 20, 5% w/v sucrose in PBS) was then addedto wells and plate incubated for 2 hours at room temperature. Blockingsolution is flicked out and plates washed three times and tapped dry.

Compound dilution series were prepared in EBM-2 (Cat #CC-3156,Lonza)+0.1% BSA (Cat#A8412, Sigma) with constant 0.1% DMSOconcentration. 439 μL of sample or vehicle control was added to the cellmonolayers. Cells are treated for 1 hour at 37° C. and 5% CO₂. 250 ng/mLRecombinant human VEGFC (Cat #2179-VC, R & D Systems) added to wells andplates incubated for an additional 10 minutes at 37° C. and 5% CO₂.

The media and compounds were removed and the cell monolayer washed oncein Dulbecco's Phosphate Buffered Saline (Cat #21600-044, Invitrogen).130 μL of Lysis buffer added to wells and cell lysate harvested andtransferred to tubes and stored on ice. Complete lysis buffer wasprepared by adding 10 μL Protease Inhibitor Cocktail (Cat #P8340,Sigma-Aldrich), 10 μL PMSF (Phenylmethanesulfonyl fluoride, Cat #P7626,Sigma-Aldrich, prepared as 500 mM DMSO stock) per 1 mL of Phosphosafe™Extraction Reagent (Cat #71296, Merck).

The harvested samples were then diluted 1:2 in IC Diluent #18 (5% Tween20/PBS) and 100 μL transferred to the Total and Phospho VEGFR3 coated,blocked and washed 96 well plates and incubated for 2 hours at roomtemperature. The plates were then washed three times in wash buffer asdescribed above and tapped dry.

For detection of Total VEGFR3100 μL of Detection antibody (Total VEGFR3Detection Antibody Part#841888 in Total VEGFR3 kit) diluted in ICDiluent #1 (1% w/v BSA (Cat #A7906, Sigma-Aldrich)/PBS) was added towells and the plate incubated for 2 hours at room temperature. The platewas then washed three times in wash buffer and tapped dry. 100 μL ofstreptavidin-HPR diluted in IC diluent #1 Streptavidin-HRP, Part #890803in Total VEGFR3 kit) was added to wells and incubated at roomtemperature for 20 minutes followed by washing as described above 100 μLSubstrate solution (3,3′,5,5′-Tetramethylbenzidine (TMB) LiquidSubstrate System for ELISA, Cat #T0440, Sigma-Aldrich) was added and theplate incubated for 20 minutes in the dark at room temperature followedby the addition of 50 μL stop solution (2 M H₂SO₄).

Total VEGFR3 levels were quantified using a Multiskan Ascent platereader and Ascent software fitted with 450 nm filter.

For detection of Phospho VEGFR3, 100 μL of Detection antibody(Anti-Phospho-Tyrosine-HRP Detection Antibody, Part #841403 in PhosphoVEGFR3 kit) was diluted in IC Diluent #1 (1% w/v BSA/PBS), added to thewells and the plate incubated for 2 hours at room temperature. The platewas then washed three times in wash buffer as described above and tappeddry. 100 μL Substrate solution (3,3′,5,5′-Tetramethylbenzidine (TMB)Liquid Substrate System for ELISA, Cat #T0440, Sigma-Aldrich) was addedand the plate incubated for 20 minutes in the dark at room temperaturefollowed by the addition of 50 μL stop solution (2 M H2SO₄).

Phospho VEGFR3 levels were quantified using a Multiscan ascent platereader and ascent software fitted with 450 nm filter. IC₅₀ values aredetermined by first calculating the level of phospho VEGFR3 relative toTotal VEGFR3 according to the following formula:

${SRP} = \frac{SP}{ST}$

Where SRP is the Sample Relative Phospho level, SP is Phospho VEGFR3reading and ST is Total VEGFR3 reading.

Percent inhibition (% I) for each lysate relative to vehicle control(VEGFC stimulated) is then calculated according to the followingformula:

${\% \mspace{14mu} I} = {\frac{{{SRP}\mspace{14mu} {Vehicle}} - {{SRP}\mspace{14mu} {Test}}}{{SRP}\mspace{14mu} {Vehicle}}*100}$

Where SRP is the Sample Relative Phospho level as calculated above. % Iis plotted against compound concentration and data fitted using aSigmoidal dose response with IC₅₀ determined from curve.

VEGFR3 Phospho ELISA Assay Results

Compound IC50 (nM) 2 121 3 156 4 2216 5 210 6 62 9 379 11 39 12 116 131034 16 214 18 18 24 169 26 83 28 190 31 107 33 1254 37 26

VEGFR² Phospho ELISA Assay

Compounds of the invention may be tested for in vitro activity in thefollowing assay:

Adult human umbilical vein endothelial cells (HUVEC) (Cat#CC-2519,Lonza) were seeded into clear-bottom, TC treated 12 well plates (Cat#665180, Greiner Bio-One) in EGM-2 (Cat#CC-3162, Lonza) at 180,000cells/well (volume 1 mL), and the plates incubated at 37° C. and 5% CO₂for 6 hours. The media was replaced with EBM-2 (Cat #CC-3156,Lonza)+0.1% BSA (Cat#A8412, Sigma) and cells incubated for a furtherperiod (overnight at 37° C. and 5% CO₂).

96 well Maxisorp immuno plates (Cat #439454, Nunc) were coated with 100μL of Total VEGFR² capture antibody (Part #841434, Human TotalVEGFR²/FLT4 ELISA Kit, Cat #DYC1780, R&D Systems), or Phospho VEGFR²Capture antibody (Part #841419, Human Phospho VEGFR²/FLT4 ELISA Kit,Cat#DYC1766, R&D Systems). The plates were covered and incubated at roomtemperature overnight.

The coating antibody was flicked out and the plates washed three timeswith Wash Buffer (Phosphate buffered saline (137 mM NaCl, 2.7 nM KCl,8.1 nM Na₂HPO₄, 1.5 mL KH₂PO₄, pH 7.2-7.4), 0.05% Tween 20). 300 μL ofBlocking buffer (1% v/v BSA (Cat#A8412, Sigma) in PBS) was then added towells and plate incubated for 2 hours at room temperature. Blockingsolution is flicked out and plates washed three times and tapped dry.

Compound dilution series were prepared in EBM-2 (Cat #CC-3156,Lonza)+0.1% BSA (Cat#A8412, Sigma) with constant 0.1% DMSOconcentration. 427.5 μL of sample or vehicle control was added to thecell monolayers. Cells are treated for 1 hour at 37° C. and 5% CO₂. 50ng/mL Recombinant human VEGF (Cat #293-VC, R & D Systems) added to wellsand plates incubated for an additional 10 minutes at 37° C. and 5% CO₂.

The media and compounds were removed and the cell monolayer washed oncein Dulbecco's Phosphate Buffered Saline (Cat #21600-044, Invitrogen).130 μL of Lysis buffer added to wells and cell lysate harvested andtransferred to tubes and stored on ice. Complete lysis buffer wasprepared by adding 10 μL Protease Inhibitor Cocktail (Cat #P8340,Sigma-Aldrich), 10 μL PMSF (Phenylmethanesulfonyl fluoride, Cat #P7626,Sigma-Aldrich, prepared as 500 mM DMSO stock) per 1 mL of Phosphosafe™Extraction Reagent (Cat #71296, Merck).

The harvested samples were then diluted 1:2 in IC Diluent #12 (1% NP-40,20 nM Tris (pH 8.0), 137 mM NaCl, 10% glycerol, 2 mM EDTA, 1 mMactivated sodium orthovanadate) and 100 μL transferred to the Total andPhospho VEGFR² coated, blocked and washed 96 well plates and incubatedfor 2 hours at room temperature. The plates were then washed three timesin wash buffer as described above and tapped dry.

For detection of Total VEGFR²100 μL of Detection antibody (Total VEGFR²Detection Antibody Part#841435 in Total VEGFR² kit) diluted in ICDiluent #14 (20 mM Tris, 137 mM CaCl, 0.05% Tween20, 0.1% BSA) was addedto wells and the plate incubated for 2 hours at room temperature. Theplate was then washed three times in wash buffer and tapped dry. 100 μLof streptavidin-HPR diluted in IC diluent #14 Streptavidin-HRP, Part#890803 in Total VEGFR² kit) was added to wells and incubated at roomtemperature for 20 minutes followed by washing as described above. 100μL Substrate solution (3,3′,5,5′-Tetramethylbenzidine (TMB) LiquidSubstrate System for ELISA, Cat #T0440, Sigma-Aldrich) was added and theplate incubated for 20 minutes in the dark at room temperature followedby the addition of 50 μL stop solution (2 M H₂SO₄).

Total VEGFR² levels were quantified using a Multiskan Ascent platereader and Ascent software fitted with 450 nm filter.

For detection of Phospho VEGFR², 100 μL of Detection antibody(Anti-Phospho-Tyrosine-HRP Detection Antibody, Part #841403 in PhosphoVEGFR² kit) was diluted in IC Diluent 14 (20 mM Tris, 137 mM Ca2Cl,0.05% Tween20, 0.1% BSA), was added to the wells and the plate incubatedfor 2 hours at room temperature. The plate was then washed three timesin wash buffer as described above and tapped dry. 100 μL Substratesolution (3,3′,5,5′-Tetramethylbenzidine (TMB) Liquid Substrate Systemfor ELISA, Cat #T0440, Sigma-Aldrich) was added and the plate incubatedfor 20 minutes in the dark at room temperature followed by the additionof 50 μL stop solution (2 M H₂SO₄). Phospho VEGFR² levels werequantified using a Multiscan ascent plate reader and ascent softwarefitted with 450 nm filter. IC₅₀ values are determined by firstcalculating the level of phospho VEGFR² relative to Total VEGFR²according to the following formula:

${SRP} = \frac{SP}{ST}$

where SRP is the Sample Relative Phospho level, SP is Phospho VEGFR²reading and ST is Total VEGFR² reading.

Percent inhibition (% I) for each lysate relative to vehicle control(VEGF-A stimulated) is then calculated according to the followingformula:

${\% \mspace{14mu} I} = {\frac{{{SRP}\mspace{14mu} {Vehicle}} - {{SRP}\mspace{14mu} {Test}}}{{SRP}\mspace{14mu} {Vehicle}}*100}$

where SRP is the Sample Relative Phospho level as calculated above.

% I is plotted against compound concentration and data fitted using aSigmoidal dose response with IC₅₀ determined from plotted curve.

VEGFR² Phospho ELISA Assay Results

Compound IC₅₀ (nM) 2 4397 4 >10000 18 2548 24 >10000 26 4071 28 6840 315100 33 >10000 37 200

P397Y-FAK Inhibition MSD Platform Cellular Biomarker Assay

Compounds of the invention may be tested for in vitro activity in thefollowing assay:

96-well plates (cat#MA6000, Meso Scale Discovery) are coated with 30μL/well of mouse monoclonal FAK antibody [63D5] (cat#ab72140, Abcam)pre-diluted in PBS to a concentration of 1 mg/mL. The plates are sealedwith adhesive film and incubated for 16 hours at 4° C. The antibody isthen flicked out of the plates and 150 μL of 3% [w/v] Blocker A(cat#R93AA-1, Meso Scale Discovery) is added. The plates are resealedwith adhesive film and incubated at room temperature on a shaker set atmedium speed for 2 hours. The plates are then washed three times with asolution containing 50 mM Tris-HCl pH 7.5, 0.15 M NaCl and 0.02%Tween-20, before cell lysate addition described below.

Cells are split 1:2 into T150 cell culture flasks 2 days prior tocompound treatment. On the day prior to compound treatment, 200 μL mediacontaining 20,000 cells is seeded into all wells of white, clear-bottom,TC treated, pclear, 96-well microtitre plates (cat#655098, GreinerBio-One), and the plates are incubated at 37° C. and 5% CO₂ for 36hours. 1 pUwell of compound is then added from dilution series preparedin DMSO. Negative control wells receive the same volume of DMSO withoutcompounds, and positive control wells receive 2 μM of a control compoundin the same volume of DMSO. Cells are treated for 1 hour at 37° C. and5% CO₂. The media/compounds are then flicked off and 55 pUwell ofice-cold complete lysis buffer is added. Complete lysis buffer isprepared by adding 1 tablet PhosSTOP complete phosphatase inhibitor(cat#04906837001, Roche) and 1 tablet Complete, Mini, EDTA-free,protease inhibitor (cat#04693159001, Roche) per 10 mL of incompletelysis buffer (150 mM NaCl, 20 mM Tris-HCl pH 7.5, 1 mM EDTA, 1 mM EGTA,1% Triton-X 100). Plates are incubated on ice for 30 minutes, with 30seconds high speed plate shaking every 5 minutes. 40 μL/well of celllysate is transferred to the coated, blocked and washed 96-wellmicrotitre plates described above. The 96-well plates are sealed withadhesive film and incubated for 16 hours at 4° C. The plates are thenwashed three times with a solution containing 50 mM Tris-HCl pH 7.5,0.15 M NaCl and 0.02% Tween-20 and tapped dry. 25 μL/well of detectionsolution (1% [w/v] Blocker A (cat#R93AA-1, Meso Scale Discovery) in 50mM Tris-HCl pH 7.5, 0.15 M NaCl and 0.02% Tween-20, with 1:600 rabbitpolyclonal FAK phospho Y397 antibody (cat#ab39967, Abcam), 1:1000anti-rabbit sulfo-tag antibody (cat#R32AB-1 Meso Scale Discovery) and1:40 reconstituted Blocker D-M (cat#D609-0100, Rockland Immunochemicalsfor Research)) is added, and the plates resealed with adhesive film andincubated for 1 hour at room temperature on a plate shaker set to mediumspeed. Plates are then washed three times with a solution containing 50mM Tris-HCl pH 7.5, 0.15 M NaCl and 0.02% Tween-20 and tapped dry. 150μL/well of Read Buffer T+Surfactant (cat#R92TC-1, Meso Scale Discovery)is then added, and pFAK-397 levels quantified using a Meso ScaleDiscovery SECTOR Imager 6000 instrument.

IC₅₀ values are determined by first calculating percent inhibition (% I)for each lysate relative to controls on the same plate (%I=(S-CP)/(CN-CP)) where S is the sample result, CN is the average resultof DMSO only treated negative controls, and CP is the average result of2 μM treated positive controls. % I is plotted against compoundconcentration [I] and the data fitted using the following equation, %I=(A+((B−A)/(1+((C/[I])̂D)))), where A is the lower asymptote, B is theupper asymptote, C is the IC₅₀ value, and D is the slope factor.

P397Y-FAK Inhibition MSD Platform Cellular Biomarker Assay Results forMDA-231-LNA Cells

Compound IC₅₀ (nM) 3 62 5 >2000 6 940 11 16 12 30 16 >2000 18 25 19 7 20<50% 21 119 22 944 24 >2000 26 >2000 28 >2000 31 >2000 33 >2000

1-64. (canceled)
 65. A compound of the formula (I) or a stereoisomer,salt, solvate or prodrug thereof:

wherein: A is an optionally substituted 5-10 membered heteroaryl grouplinked to the NH group through an aromatic ring carbon atom, in whichthe heteroaryl ring system contains 1 to 4 heteroatoms selected from thegroup consisting of N, O and S, and; A may bear a substituent R^(1A)which is not alpha to the NH group and may optionally further bear one,two or three substituents Rlc which are not alpha to the NH group, whereR^(1A) is selected from the group consisting of: (i) CH(R^(C1))NHZ¹,where R^(C1) is H or C₁₋₂ alkyl, and Z¹ is selected from the groupconsisting of H, C₁₋₃ alkyl optionally substituted by OH, C(═O)OC₁₋₃alkyl and C(═O)Me; (ii) XNHZ², where X is selected from the groupconsisting of CMe₂, cyclopropylidene, cyclobutylidene, cyclopentylideneand oxetanylidine, and Z² is selected from the group consisting of H,C₁₋₃ alkyl optionally substituted by OH, C(═O)OC₁₋₃ alkyl and C(═O)Me;and (iii) a group selected from the group consisting of:

wherein: R^(N1) is H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl or C(═O)Me; R^(N2) isH, C₁₋₄ alkyl, C₃₋₄ cycloalkyl or C(═O)Me; R^(N3) is H, C₁₋₄ alkyl, C₃₋₄cycloalkyl or C(═O)Me; R^(N4) is H or methyl; R^(N5) is selected fromthe group consisting of H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and C(═O)Me;R^(N6) is selected from the group consisting of H, C₁₋₄ alkyl, C₃₋₄cycloalkyl and C(═O)Me; R^(N7) and R^(N8) are each independently H ormethyl; R^(N9) is selected from the group consisting of H, C₁₋₄ alkyl,C₃₋₄ cycloalkyl and C(═O)Me; R^(N10) is selected from the groupconsisting of H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and C(═O)Me; R^(N11) isselected from the group consisting of H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl andC(═O)Me; and R^(N12) is selected from the group consisting of H, C₁₋₄alkyl, C₃₋₄ cycloalkyl and C(═O)Me; and each R^(1C) is independentlyselected from the group consisting of C₁₋₃ alkyl, CF₃, F, CI, O—(C₁₋₃alkyl), CN, and ═O; R² is selected from the group consisting of H, halo,C₁₋₄ alkyl, CF₃, CF₂H, CN and methoxy; R³ is a substituted phenyl or asubstituted 6-membered heteroaryl group, where the heteroaryl ringsystem contains 1 or 2 N heteroatoms, where R³ bears a substituent R⁴either alpha or beta to the —C₂H₄— group, and may additionally bearfurther substituents selected from the group consisting of F, methyl andCF₃; and R⁴ is —CH₂—C(O)N(R^(N13))Z³, where R^(N13) is H or methyl; andZ³ is H, methyl or methoxy.
 66. A compound according to claim 65, withthe proviso that it is not one of the following compounds:


67. A compound according to claim 65, wherein A is an optionallysubstituted 6-membered heteroaryl group.
 68. A compound according toclaim 67, wherein A is optionally substituted pyridyl.
 69. A compoundaccording to claim 68, wherein A is selected from the group consistingof:


70. A compound according to claim 69, wherein A is


71. A compound according to claim 65, wherein A is an optionallysubstituted 5-membered heteroaryl group.
 72. A compound according toclaim 71, wherein A is optionally substituted pyrazolyl.
 73. A compoundaccording to claim 72, wherein A is selected from the group consistingof:


74. A compound according to claim 73, wherein A is


75. A compound according to claim 65, where no Rlc substituents arepresent on A.
 76. A compound according to claim 65, where R^(1C) ismethyl.
 77. A compound according to claim 65, where a single R^(1C)substituent is present.
 78. A compound of formula (II) or astereoisomer, salt, solvate or prodrug thereof:

wherein: A is optionally substituted phenyl; when A is a substitutedphenyl, A may bear a substituent R^(1A) which is not alpha to the NHgroup and may optionally further bear one or two substituents R whichare not alpha to the NH group, R^(1A) is selected from the groupconsisting of: (i) CH(R^(C1))NHZ¹, where R^(C1) is H or C₁₋₂ alkyl, andZ¹ is selected from the group consisting of H, C₁₋₃ alkyl optionallysubstituted by OH, C(═O)OC₁₋₃ alkyl and C(═O)Me; (ii) XNHZ², where X isselected from the group consisting of CMe₂, cyclopropylidene,cyclobutylidene, cyclopentylidene and oxetanylidine and Z is selectedfrom the group consisting of H, C₁₋₃ alkyl optionally substituted by OH,C(═O)OC₁₋₃ alkyl and C(═O)Me; and (iii) a group selected from the groupconsisting of:

wherein: R^(N1) is selected from the group consisting of H, C₁₋₄ alkyl,C₃₋₄ cycloalkyl and C(═O)Me; R^(N2) is selected from the groupconsisting of H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and C(═O)Me; R^(N3) isselected from the group consisting of H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl andC(═O)Me; R^(N4) is H or methyl; R^(N5) is selected from the groupconsisting of H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and C(═O)Me; R^(N6) isselected from the group consisting of H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl andC(═O)Me; R^(N7) and R^(N8) are each independently H or methyl; R^(N9) isselected from the group consisting of H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl andC(═O)Me; R^(N10) is selected from the group consisting of H, C₁₋₄ alkyl,C₃₋₄ cycloalkyl and C(═O)Me; R^(N11) is selected from the groupconsisting of H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl and C(═O)Me; and R^(N12) isselected from the group consisting of H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl andC(═O)Me; and where each R_(1B) is independently selected from the groupconsisting of C₁₋₃ alkyl, CF₃, F, Cl, O—(C₁₋₃ alkyl), and CN; R² isselected from the group consisting of H, halo, C₁₋₄ alkyl, CF₃, CF₂H, CNand methoxy; R³ is a substituted phenyl or a substituted 6-memberedheteroaryl group, where the heteroaryl ring system contains 1 or 2 Nheteroatoms, where R³ bears a substituent R⁴ either alpha or beta to the—C₂H₄— group, and may additionally bear further substituents selectedfrom F, methyl and CF₃; and R⁴ is —CH₂—C(O)N(R^(N13))Z³, where R^(N13)is H or methyl; and Z³ is H, methyl or methoxy.
 79. A compound accordingto claim 78, with the proviso it is not any of the following compounds:


80. A compound according to claim 78, with the proviso that: when R³ isselected from the group consisting of:

A is (i)

where R^(1A) is selected from

and R^(N1) is H, C₁₋₃ alkyl, or C(═O)Me; R^(N2) is H, C₁₋₃ alkyl, orC(═O)Me; R^(N3) is H, C₁₋₃ alkyl, or C(═O)Me; R^(N4) is H or methyl;R^(N5) is H, C₁₋₃ alkyl, or C(═O)Me; R^(N7) and R^(N8) are eachindependently H or methyl; R^(N9) is H, C₁₋₃ alkyl, or C(═O)Me; R^(N10)is H, C₁₋₃ alkyl, or C(═O)Me; Or A is (ii)

where R^(1A) is

R^(N1) is H, C₁₋₃ alkyl, or C(═O)Me; and R^(N2) is H, C₁₋₃ alkyl, orC(═O)Me; then R² is not CF₃, halo, CF₂H or CN.
 81. A compound accordingto claim 78, wherein A is selected from the group consisting of:


82. A compound according to claim 78, where no R^(1B) substituents arepresent on A.
 83. A compound according to claim 78, where R^(1B) ismethyl.
 84. A compound according to claim 78, where a single R_(1B)substituent is present.
 85. A compound according to claim 65, whereinR^(1A) is selected from the group consisting of:

wherein R^(N1) is C(═O)Me,

wherein R^(N1) is H, methyl or ethyl,

wherein R^(N2) is H, methyl or ethyl,

wherein R^(N3) is H or methyl,

wherein R^(N4) is H or methyl,

wherein R^(N5) is H or methyl,

wherein R^(N6) is H or methyl,

wherein R^(N7) and R^(N8) are both H or both methyl,

wherein R^(N9) is H,

wherein R^(N10) is H or methyl,

wherein RN¹¹ is H or methyl, and

where R^(N12) is H or methyl.
 86. A compound according to claim 65,wherein R^(1A) is selected from the group consisting of:


87. A compound according to claim 65, wherein R² is H.
 88. A compoundaccording to claim 87, wherein R² is methyl.
 89. A compound according toclaim 87, wherein R² is CF₃.
 90. A compound according to claim 65,wherein R³ is

R⁶, R⁷ and R⁸ are each independently selected from the group consistingof H, F, methyl and CF₃; and one of R^(4A) and R^(4B) is R⁴, and theother of R^(4A) and R^(4B) is H, F, methyl or CF₃.
 91. A compoundaccording to claim 65, wherein R is a substituted 6-membered heteroarylgroup, where the heteroaryl ring system contains 1 or 2 N heteroatoms.92. A compound according to claim 91, wherein R is selected from thegroup consisting of

where each of R⁶, R⁷ and R⁸ (if present) are independently H, F, methylor CF₃; and one of R^(4A) and R^(4B) (if present) is R⁴, and the otheris H, F, methyl or CF₃.
 93. A compound according to claim 65 wherein: Ais an optionally substituted 5- or 6-membered heteroaryl group linked tothe NH group through an aromatic ring carbon atom, in which theheteroaryl ring system contains 1 or 2 N atoms, and A may bear asubstituent R^(1A) which is not alpha to the NH group and may optionallyfurther bear a substituent R^(1C) which are not alpha to the NH group,where R^(1A) is selected from the group consisting of: (i)CH(R^(C1))NHZ¹, where R^(C1) is C₁₋₂ alkyl and Z¹ is H or C₁₋₃ alkyloptionally substituted by OH; (ii) XNHZ², where X is cyclobutylidene,and Z² is C(═O)OC₁₋₃ alkyl; (iii) a group R^(1A2) or R^(1A6) :

wherein: R^(N2) is H or C₁₋₄ alkyl; R^(N6) is H; and where R^(1C) isC₁₋₃ alkyl; R² is C₁₋₄ alkyl or CF₃; R³ is substituted phenyl, where R³bears a substituent R⁴ alpha to the —C₂H₄— group, and may additionallybear a further substituent F; and R⁴ is —CH₂—C(O)NH₂.
 94. A compoundaccording to claim 65 wherein: A is an optionally substituted 5- or6-membered heteroaryl group linked to the NH group through an aromaticring carbon atom, in which the heteroaryl ring system contains 1 or 2 Natoms, and A may bear a substituent

which is not alpha to the NH group and may optionally further bear asubstituent R^(1C) which are not alpha to the NH group, wherein: R^(N2)is H or C₁₋₄ alkyl; and where R^(1C) is C₁₋₃ alkyl; R² is C₁₋₄ alkyl; R³is substituted phenyl, where R³ bears a substituent R⁴ alpha to the—C₂H₄— group; and R⁴ is —CH₂—C(O)NH₂.
 95. A compound according to claim65 wherein: A is selected from the group consisting of:

wherein R^(1A) is selected from the group consisting of: (i)CH(R^(C1))NHZ¹, where R^(C1) is H or methyl and Z¹ is H or CH₂CH₂OH;(ii) XNHZ², where X is cyclobutylidene or oxetanylidine and Z is H orC(═O)OMe; and (iii) a group selected from the group consisting ofR^(1A1), R^(1A2), R^(1A6) and R^(1A11):

wherein: R^(N1) is H or Me; R^(N2) is H or Me; R^(N6) is H or Me; andR^(N12) is H or Me; and where there may be a single R^(1C) group whichis methyl; R² is H, methyl or CF₃; R³ is:

where R⁵, R⁶ and R⁷ are H, F, methyl or CF₃, and only one of them is notH; and R⁴ is —CH₂—C(O)NH₂.
 96. A compound according to claim 78 wherein:A is substituted phenyl; A may bear a substituent R^(1A) which is notalpha to the NH group and may optionally further bear a substituentR_(1B) which is not alpha to the NH group, where R^(1A) is selected fromthe group consisting of: (i) CH(R^(C1))NHZ¹, where R^(C1) is H or C₁₋₂alkyl and Z¹ is H, C₁₋₃ alkyl optionally substituted by OH, or C(═O)Me;(ii) XNHZ², where X is cyclobutylidene or oxetanylidine, and Z² is H orC(═O)OC₁₋₃ alkyl; and (iii) a group selected from the group consistingof:

wherein: R^(N1) is H; R^(N2) is H or C₁₋₄ alkyl; R^(N6) is H; R^(N11) isH; and R^(N12) is H; and where each R_(1B) is independently C₁₋₃ alkylor F; R² is selected from the group consisting of H, halo, C₁₋₄ alkyl,CF₃ and methoxy; R³ is substituted phenyl, where R³ bears a substituentR⁴ alpha to the -C₂H₄- group, and may additionally bear a furthersubstituent selected from the group consisting of F, methyl and CF₃; andR⁴ is —CH₂—C(O)NH₂.
 97. A compound according to claim 78 wherein: A issubstituted phenyl; A may bear a substituent R^(1A) which is not alphato the NH group and may optionally further bear a substituent R which isnot alpha to the NH group, where R^(1A) is selected from the groupconsisting of: (i) CH(R^(C1))NHZ¹, where R^(C1) is H or C₁₋₂ alkyl, andZ¹ is H or C₁₋₃ alkyl optionally substituted by OH; (ii) XNH₂, where Xis oxetanylidine; and (iii) a group selected from the group consistingof:

wherein: R^(N1) is H; R^(N2) is H or C₁₋₄ alkyl; R^(N6) is H; R^(N11) isH;and R^(N12) is H; and where each R^(1B) is C₁₋₃ alkyl; R² is selectedfrom the group consisting of halo, C₁₋₄ alkyl, CF₃ and methoxy; R³ issubstituted phenyl, where R bears a substituent R alpha to the —C₂H₄—group, and may additionally bear a further substituent selected from thegroup consisting of methyl and CF₃; and R⁴ is -CH₂—C(O)NH₂.
 98. Acompound according to claim 78, wherein A is

R^(1A) is selected from the group consisting of: (i) CH(R^(C1))NHZ whereR^(C1) is H or methyl, and Z¹ is H or CH₂CH₂OH; (ii) XNHZ², where X iscyclobutylidene or oxetanylidine, and Z² is H or C(═O)OMe; and (iii) agroup selected from the group consisting of R^(1A1) , R^(1A2), R^(1A6)and R^(1A11):

wherein: R^(N1) is H or Me; R^(N2) is H or Me; R^(N6) is H or Me; andR^(N12) is H or Me; and where there may be a single R_(1B) group whichis selected from the group consisting of F and methyl; R² is H, methylor CF₃; R³ is

where R⁵, R⁶ and R⁷ are H, F, methyl or CF₃, and only one of them is notH; and R⁴ is —CH₂—C(O)NH₂.
 99. A compound selected from2-(2-(2-(2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(1)2-(2-(2-(5-methyl-2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(2)2-(2-(2-(2-((4-(aminomethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(3)2-(2-(2-(5-methyl-2-((6-(piperidin-4-yl)pyridin-3-yl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(4)2-(2-(2-(5-methyl-2-((6-(1-methylpiperidin-4-yl)pyridin-3-yl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(5)2-(2-(2-(2-((4-(piperazine-1-carbonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(6)2-(2-(2-(2-((3-fluoro-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(7)2-(2-(2-(2-((3-fluoro-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(8)2-(5-fluoro-2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(9)2-(5-fluoro-2-(2-(2-((4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(10)2-(2-(2-(2-((3-methyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(11)2-(2-(2-(2-((3-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(12)2-(2-(2-(2-((6-(piperidin-4-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(13)2-(2-(2-(2-((6-(1-methylpiperidin-4-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(14)2-(4-fluoro-2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(15) 2-(2-(2-(5-methyl-2-((4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide (16)2-(2-(2-(2-((4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-4-(trifluoromethyl)phenyl)acetamide(17)2-(2-(2-(2-(4-(1-aminoethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(18)2-(2-(2-(2-((4-(((2-hydroxyethyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(19)2-(2-(2-(2-((4-(azetidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(20)2-(4-methyl-2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(21)2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-6-(trifluoromethyl)phenyl)acetamide(22)2-(2-(2-(5-methoxy-2-((4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(23)2-(2-(2-(5-methyl-2-(pyridin-3-ylamino)pyrimidin-4-yl)ethyl)phenyl)acetamide(24)2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-5-(trifluoromethyl)phenyl)acetamide (25)2-(2-(2-(5-methyl-2-((4-(piperidin-4-yloxy)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(26)2-(2-(2-(2-((4-(aminomethyl)phenyl)amino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide(27)2-(2-(2-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(28) methyl1-(4-(4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-ylamino)phenyl)cyclobutylcarbamate(29)2-(2-(2-(2-((1-(azetidin-3-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide(30)2-(2-(2-(2-(4-(3-aminooxetan-3-yl)phenylamino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide(31) 2-(2-(2-(2-((4-(azetidin-3-yl)phenyl)acetamide (32)2-(2-(2-(5-Methyl-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide(33) 2-(2-(2-(2-((4-(1-aminoethyl)phenyl)amino)-5-methylpyrimidin-4-yl)ethyl)phenyl) acetamide (34)2-(2-(2-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(35)2-(2-(2-(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide(36)2-(2-(2-(2-(4-(1-aminoethyl)phenylamino)-5-chloropyrimidin-4-yl)ethyl)phenyl)acetamide (37)2-(2-(2-(2-((3-(1-aminoethyl)phenyl)amino)-5-chloropyrimidin-4-yl)ethyl)phenyl)acetamide (38)2-(2-(2-(2-((3-(1-acetamidoethyl)phenyl)amino)-5-chloropyrimidin-4-yl)ethyl)phenyl)acetamide(39)2-(2-(2-(2-((6-(1-aminoethyl)pyridin-3-yl)amino)-5-chloropyrimidin-4-yl)ethyl)phenyl)acetamide(40)

or a stereoisomer, salt, solvate, protected form or prodrug thereof.100. A process for the preparation of a compound according to claim 65or a stereoisomer, salt, solvate or prodrug thereof, comprising reactinga compound of formula F1

with a compound of formula A-NH₂ to displace the group L1 and with acompound of formula HC≡R³ to displace the group L2, or with a compoundof formula HC≡R³ to displace the group L2 and with a compound of formulaA-NH₂ to displace the group L1, wherein L1 and L2 are leaving groups.101. A pharmaceutical agent comprising a compound according to claim 65or a stereoisomer, salt, solvate or prodrug thereof.
 102. A compositioncomprising a compound according to claim 65 or a stereoisomer, salt,solvate or prodrug thereof, and a pharmaceutically acceptable carrier ordiluent.
 103. A method for treating a disease ameliorated by theinhibition of VEGFR3 comprising administering an effective amount of acompound according to claim 65 or a stereoisomer, salt, solvate orprodrug thereof to a subject in need thereof.
 104. A method for treatingcancer comprising administering an effective amount of a compoundaccording to claim 65 or a stereoisomer, salt, solvate or prodrugthereof to a subject in need thereof.
 105. A method of inhibiting VEGFR3in vitro or in vivo, comprising contacting a cell with an effectiveamount of a compound according to claim 65 or a stereoisomer, salt,solvate or prodrug thereof.
 106. The method of claim 104, wherein thecancer is selected from the group consisting of melanoma, breast cancerand cancer of the head or neck.
 107. An anti-cancer agent comprising acompound according to claim 65 or a stereoisomer, salt, solvate orprodrug thereof and an anti-tumor agent.